A Structural Framework for GPCR Chemogenomics: What’s In a Residue Number?

  • Márton Vass
  • Albert J. Kooistra
  • Stefan Verhoeven
  • David Gloriam
  • Iwan J. P. de Esch
  • Chris de Graaf
Part of the Methods in Molecular Biology book series (MIMB, volume 1705)


The recent surge of crystal structures of G protein-coupled receptors (GPCRs), as well as comprehensive collections of sequence, structural, ligand bioactivity, and mutation data, has enabled the development of integrated chemogenomics workflows for this important target family. This chapter will focus on cross-family and cross-class studies of GPCRs that have pinpointed the need for, and the implementation of, a generic numbering scheme for referring to specific structural elements of GPCRs. Sequence- and structure-based numbering schemes for different receptor classes will be introduced and the remaining caveats will be discussed. The use of these numbering schemes has facilitated many chemogenomics studies such as consensus binding site definition, binding site comparison, ligand repurposing (e.g. for orphan receptors), sequence-based pharmacophore generation for homology modeling or virtual screening, and class-wide chemogenomics studies of GPCRs.

Key words

G protein-coupled receptors GPCRs Crystal structures Chemogenomics Drug discovery Ligand repurposing Numbering schemes Mutations 



Netherlands eScience Center/NWO (3D-e-Chem, grant 027.014.201, to C.d.G). M. V., A. J. K., D. G., I. J. P. d. E. and C. d. G. participate in the COST Action CM1207 (GLISTEN). M. V., D. G., and C. d. G. participate in the GPCR Consortium ( Vignir Isberg and Christian Munk (GPCRdb (, University of Copenhagen) are acknowledged for useful discussions on the developments of the GPCRdb KNIME nodes.


  1. 1.
    Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3(9):639–650. PubMedCrossRefGoogle Scholar
  2. 2.
    Stevens RC, Cherezov V, Katritch V, Abagyan R, Kuhn P, Rosen H, Wuthrich K (2013) The GPCR network: a large-scale collaboration to determine human GPCR structure and function. Nat Rev Drug Discov 12(1):25–34. PubMedCrossRefGoogle Scholar
  3. 3.
    Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993–996. PubMedCrossRefGoogle Scholar
  4. 4.
    Rask-Andersen M, Masuram S, Schioth HB (2014) The druggable genome: evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu Rev Pharmacol Toxicol 54:9–26. PubMedCrossRefGoogle Scholar
  5. 5.
    Garland SL (2013) Are GPCRs still a source of new targets? J Biomol Screen 18(9):947–966. PubMedCrossRefGoogle Scholar
  6. 6.
    Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE (2017) Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. In pressGoogle Scholar
  7. 7.
    Lv X, Liu J, Shi Q, Tan Q, Wu D, Skinner JJ, Walker AL, Zhao L, Gu X, Chen N, Xue L, Si P, Zhang L, Wang Z, Katritch V, Liu ZJ, Stevens RC (2016) In vitro expression and analysis of the 826 human G protein-coupled receptors. Protein Cell 7(5):325–337. PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Chung S, Funakoshi T, Civelli O (2008) Orphan GPCR research. Br J Pharmacol 153(Suppl 1):S339–S346. PubMedGoogle Scholar
  9. 9.
    Roth BL, Kroeze WK (2015) Integrated approaches for genome-wide interrogation of the Druggable non-olfactory G protein-coupled receptor superfamily. J Biol Chem 290(32):19471–19477. PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR, Pin JP, Spedding M, Harmar AJ (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev 65(3):967–986. PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Attwood TK, Findlay JB (1994) Fingerprinting G-protein-coupled receptors. Protein Eng 7(2):195–203PubMedCrossRefGoogle Scholar
  12. 12.
    Kolakowski LF Jr (1994) GCRDb: a G-protein-coupled receptor database. Receptors Channels 2(1):1–7PubMedGoogle Scholar
  13. 13.
    Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63(6):1256–1272. PubMedCrossRefGoogle Scholar
  14. 14.
    Nordstrom KJ, Sallman Almen M, Edstam MM, Fredriksson R, Schioth HB (2011) Independent HHsearch, Needleman--Wunsch-based, and motif analyses reveal the overall hierarchy for most of the G protein-coupled receptor families. Mol Biol Evol 28 (9):2471–2480. doi:
  15. 15.
    Tautermann CS (2014) GPCR structures in drug design, emerging opportunities with new structures. Bioorg Med Chem Lett 24(17):4073–4079. PubMedCrossRefGoogle Scholar
  16. 16.
    Hollenstein K, de Graaf C, Bortolato A, Wang MW, Marshall FH, Stevens RC (2014) Insights into the structure of class B GPCRs. Trends Pharmacol Sci 35(1):12–22. PubMedCrossRefGoogle Scholar
  17. 17.
    Leach K, Gregory KJ (2016) Molecular insights into allosteric modulation of class C G protein-coupled receptors. Pharmacol Res.
  18. 18.
    Harpsoe K, Boesgaard MW, Munk C, Brauner-Osborne H, Gloriam DE (2016) Structural insight to mutation effects uncover a common allosteric site in class C GPCRs. Bioinformatics.
  19. 19.
    Wang C, Wu H, Evron T, Vardy E, Han GW, Huang XP, Hufeisen SJ, Mangano TJ, Urban DJ, Katritch V, Cherezov V, Caron MG, Roth BL, Stevens RC (2014) Structural basis for smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun 5:4355. PubMedPubMedCentralGoogle Scholar
  20. 20.
    McCabe JM, Leahy DJ (2015) Smoothened goes molecular: new pieces in the hedgehog signaling puzzle. J Biol Chem 290(6):3500–3507. PubMedCrossRefGoogle Scholar
  21. 21.
    Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289(5480):739–745PubMedCrossRefGoogle Scholar
  22. 22.
    Zhou XE, Gao X, Barty A, Kang Y, He Y, Liu W, Ishchenko A, White TA, Yefanov O, Han GW, Xu Q, de Waal PW, Suino-Powell KM, Boutet S, Williams GJ, Wang M, Li D, Caffrey M, Chapman HN, Spence JC, Fromme P, Weierstall U, Stevens RC, Cherezov V, Melcher K, HE X (2016) X-ray laser diffraction for structure determination of the rhodopsin-arrestin complex. Sci Data 3:160021. PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Warne T, Moukhametzianov R, Baker JG, Nehme R, Edwards PC, Leslie AG, Schertler GF, Tate CG (2011) The structural basis for agonist and partial agonist action on a beta(1)-adrenergic receptor. Nature 469(7329):241–244. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477(7366):549–555. PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S (2011) Structure of the human histamine H1 receptor complex with doxepin. Nature 475(7354):65–70. PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330(6007):1066–1071. PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Zheng Y, Qin L, Zacarias NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, Ijzerman AP, Heitman LH, Tebben A, Kufareva I, Handel TM (2016) Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature 540(7633):458–461. PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature 499(7459):444–449. PubMedCrossRefGoogle Scholar
  29. 29.
    Jazayeri A, Dore AS, Lamb D, Krishnamurthy H, Southall SM, Baig AH, Bortolato A, Koglin M, Robertson NJ, Errey JC, Andrews SP, Teobald I, Brown AJ, Cooke RM, Weir M, Marshall FH (2016) Extra-helical binding site of a glucagon receptor antagonist. Nature 533(7602):274–277. PubMedCrossRefGoogle Scholar
  30. 30.
    Hollenstein K, Kean J, Bortolato A, Cheng RK, Dore AS, Jazayeri A, Cooke RM, Weir M, Marshall FH (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 499(7459):438–443. PubMedCrossRefGoogle Scholar
  31. 31.
    Dore AS, Bortolato A, Hollenstein K, Cheng RK, Read RJ, Marshall FH (2017) Decoding Corticotropin-releasing factor receptor type 1 crystal structures. Curr Mol Pharmacol.
  32. 32.
    Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC (2014) Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344(6179):58–64. PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Dore AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, Errey JC, Jazayeri A, Khan S, Tehan B, Weir M, Wiggin GR, Marshall FH (2014) Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511(7511):557–562. PubMedCrossRefGoogle Scholar
  34. 34.
    Christopher JA, Aves SJ, Bennett KA, Dore AS, Errey JC, Jazayeri A, Marshall FH, Okrasa K, Serrano-Vega MJ, Tehan BG, Wiggin GR, Congreve M (2015) Fragment and structure-based drug discovery for a class C GPCR: discovery of the mGlu5 negative allosteric modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem 58(16):6653–6664. PubMedCrossRefGoogle Scholar
  35. 35.
    Wang C, Wu H, Katritch V, Han GW, Huang XP, Liu W, Siu FY, Roth BL, Cherezov V, Stevens RC (2013) Structure of the human smoothened receptor bound to an antitumour agent. Nature 497(7449):338–343. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Weierstall U, James D, Wang C, White TA, Wang D, Liu W, Spence JC, Bruce Doak R, Nelson G, Fromme P, Fromme R, Grotjohann I, Kupitz C, Zatsepin NA, Liu H, Basu S, Wacker D, Han GW, Katritch V, Boutet S, Messerschmidt M, Williams GJ, Koglin JE, Marvin Seibert M, Klinker M, Gati C, Shoeman RL, Barty A, Chapman HN, Kirian RA, Beyerlein KR, Stevens RC, Li D, Shah ST, Howe N, Caffrey M, Cherezov V (2014) Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography. Nat Commun 5:3309. PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Byrne EF, Sircar R, Miller PS, Hedger G, Luchetti G, Nachtergaele S, Tully MD, Mydock-McGrane L, Covey DF, Rambo RP, Sansom MS, Newstead S, Rohatgi R, Siebold C (2016) Structural basis of smoothened regulation by its extracellular domains. Nature 535(7613):517–522. PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM (2013) Molecular signatures of G-protein-coupled receptors. Nature 494(7436):185–194. PubMedCrossRefGoogle Scholar
  39. 39.
    Piscitelli CL, Kean J, de Graaf C, Deupi X (2015) A molecular Pharmacologist’s guide to G protein-coupled receptor crystallography. Mol Pharmacol 88(3):536–551. PubMedCrossRefGoogle Scholar
  40. 40.
    Munk C, Harpsoe K, Hauser AS, Isberg V, Gloriam DE (2016) Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr Opin Pharmacol 30:51–58. PubMedCrossRefGoogle Scholar
  41. 41.
    Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC (2014) Allosteric sodium in class a GPCR signaling. Trends Biochem Sci 39(5):233–244. PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Gimpl G (2016) Interaction of G protein coupled receptors and cholesterol. Chem Phys Lipids 199:61–73. PubMedCrossRefGoogle Scholar
  43. 43.
    Tehan BG, Bortolato A, Blaney FE, Weir MP, Mason JS (2014) Unifying family a GPCR theories of activation. Pharmacol Ther 143(1):51–60. PubMedCrossRefGoogle Scholar
  44. 44.
    Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7(4):339–357. PubMedCrossRefGoogle Scholar
  45. 45.
    Conn PJ, Christopoulos A, Lindsley CW (2009) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8(1):41–54. PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Isberg V, de Graaf C, Bortolato A, Cherezov V, Katritch V, Marshall FH, Mordalski S, Pin JP, Stevens RC, Vriend G, Gloriam DE (2015) Generic GPCR residue numbers – aligning topology maps while minding the gaps. Trends Pharmacol Sci 36(1):22–31. PubMedCrossRefGoogle Scholar
  47. 47.
    Gloriam DE, Foord SM, Blaney FE, Garland SL (2009) Definition of the G protein-coupled receptor transmembrane bundle binding pocket and calculation of receptor similarities for drug design. J Med Chem 52(14):4429–4442. PubMedCrossRefGoogle Scholar
  48. 48.
    Kooistra AJ, Kuhne S, de Esch IJ, Leurs R, de Graaf C (2013) A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design. Br J Pharmacol 170(1):101–126. PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Ballesteros JA, Weinstein H (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci 25:366–428CrossRefGoogle Scholar
  50. 50.
    Oliveira L, Paiva ACM, Vriend GJ (1993) A common motif in G-protein-coupled seven transmembrane helix receptors. J Comput Aided Mol Des 7(6):649–658CrossRefGoogle Scholar
  51. 51.
    Baldwin JM (1993) The probable arrangement of the helices in G protein-coupled receptors. EMBO J 12(4):1693–1703PubMedPubMedCentralGoogle Scholar
  52. 52.
    Baldwin JM, Schertler GF, Unger VM (1997) An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. J Mol Biol 272(1):144–164. PubMedCrossRefGoogle Scholar
  53. 53.
    Schwartz TW (1994) Locating ligand-binding sites in 7TM receptors by protein engineering. Curr Opin Biotechnol 5(4):434–444PubMedCrossRefGoogle Scholar
  54. 54.
    Schwartz TW, Gether U, Schambye HT, Hjorth SA (1995) Molecular mechanism of action of non-peptide ligands for peptide receptors. Curr Pharm Des 1(3):325–342Google Scholar
  55. 55.
    Henderson R, Baldwin JM, Ceska TA, Zemlin F, Beckmann E, Downing KH (1990) Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J Mol Biol 213(4):899–929. PubMedCrossRefGoogle Scholar
  56. 56.
    Schertler GF, Villa C, Henderson R (1993) Projection structure of rhodopsin. Nature 362(6422):770–772. PubMedCrossRefGoogle Scholar
  57. 57.
    Unger VM, Hargrave PA, Baldwin JM, Schertler GF (1997) Arrangement of rhodopsin transmembrane alpha-helices. Nature 389(6647):203–206. PubMedCrossRefGoogle Scholar
  58. 58.
    Wootten D, Simms J, Miller LJ, Christopoulos A, Sexton PM (2013) Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations. Proc Natl Acad Sci U S A 110(13):5211–5216. PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Pin JP, Galvez T, Prezeau L (2003) Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther 98(3):325–354PubMedCrossRefGoogle Scholar
  60. 60.
    de Graaf C, Nijmeijer S, Wolf S, Ernst OP (2016) 7TM Domain structure of adhesion GPCRs. Handb Exp Pharmacol 234:43–66. PubMedCrossRefGoogle Scholar
  61. 61.
    Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S (2012) Action of molecular switches in GPCRs – theoretical and experimental studies. Curr Med Chem 19(8):1090–1109PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Venkatakrishnan AJ, Deupi X, Lebon G, Heydenreich FM, Flock T, Miljus T, Balaji S, Bouvier M, Veprintsev DB, Tate CG, Schertler GF, Babu MM (2016) Diverse activation pathways in class a GPCRs converge near the G-protein-coupling region. Nature 536(7617):484–487. PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, Wong T, Chiang V, Luis E, Estevez A, Rondon J, Zhang Y, Hotzel I, Allan BB (2012) Molecular basis for negative regulation of the glucagon receptor. Proc Natl Acad Sci U S A 109(36):14393–14398. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S, Jingami H, Morikawa K (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407(6807):971–977. PubMedCrossRefGoogle Scholar
  65. 65.
    Muto T, Tsuchiya D, Morikawa K, Jingami H (2007) Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A 104(10):3759–3764. PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Isberg V, Mordalski S, Munk C, Rataj K, Harpsoe K, Hauser AS, Vroling B, Bojarski AJ, Vriend G, Gloriam DE (2016) GPCRdb: an information system for G protein-coupled receptors. Nucleic Acids Res 44(D1):D356–D364. PubMedCrossRefGoogle Scholar
  67. 67.
    Munk C, Isberg V, Mordalski S, Harpsoe K, Rataj K, Hauser AS, Kolb P, Bojarski AJ, Vriend G, Gloriam DE (2016) GPCRdb: the G protein-coupled receptor database – an introduction. Br J Pharmacol 173(14):2195–2207. PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Lee J, Sands ZA, Biggin PC (2016) A numbering system for MFS transporter proteins. Front Mol Biosci 3:21. PubMedPubMedCentralGoogle Scholar
  69. 69.
    Randolph AL, Mokrab Y, Bennett AL, Sansom MS, Ramsey IS (2016) Proton currents constrain structural models of voltage sensor activation. elife 5.
  70. 70.
    Berthod M, Cebron N, Dill F, Gabriel T, Kötter T, Meinl T, Ohl P, Sieb C, Thiel K, Wiswedel B (2007) KNIME: the Konstanz information miner. Studies in classification, data analysis, and knowledge organization. Springer, Berlin, Heidelberg Google Scholar
  71. 71.
    Verhoeven S, Kooistra AJ, Vass M, McGuire R, Ritschel T, de Graaf C (2017) 3D-e-Chem/knime-gpcrdb: v1.1.0. Zenodo.
  72. 72.
    McGuire R, Verhoeven S, Vass M, Vriend G, De Esch IJ, Lusher SJ, Leurs R, Ridder L, Kooistra AJ, Ritschel T, de Graaf C (2017) 3D-E-Chem-VM: structural cheminformatics research infrastructure in a freely available virtual machine. J Chem Inf Model.
  73. 73.
    Bondensgaard K, Ankersen M, Thogersen H, Hansen BS, Wulff BS, Bywater RP (2004) Recognition of privileged structures by G-protein coupled receptors. J Med Chem 47(4):888–899. PubMedCrossRefGoogle Scholar
  74. 74.
    Frimurer TM, Ulven T, Elling CE, Gerlach LO, Kostenis E, Hogberg T (2005) A physicogenetic method to assign ligand-binding relationships between 7TM receptors. Bioorg Med Chem Lett 15(16):3707–3712. PubMedCrossRefGoogle Scholar
  75. 75.
    Frimurer TM, Hogberg T (2011) Drug design of GPCR ligands using physicogenetics and chemogenomics – principles and case studies. Curr Top Med Chem 11(15):1882–1901PubMedCrossRefGoogle Scholar
  76. 76.
    Zhang H, Unal H, Desnoyer R, Han GW, Patel N, Katritch V, Karnik SS, Cherezov V, Stevens RC (2015) Structural basis for ligand recognition and functional selectivity at angiotensin receptor. J Biol Chem 290(49):29127–29139. PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Zhang H, Unal H, Gati C, Han GW, Liu W, Zatsepin NA, James D, Wang D, Nelson G, Weierstall U, Sawaya MR, Xu Q, Messerschmidt M, Williams GJ, Boutet S, Yefanov OM, White TA, Wang C, Ishchenko A, Tirupula KC, Desnoyer R, Coe J, Conrad CE, Fromme P, Stevens RC, Katritch V, Karnik SS, Cherezov V (2015) Structure of the angiotensin receptor revealed by serial femtosecond crystallography. Cell 161(4):833–844. PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Receveur JM, Bjurling E, Ulven T, Little PB, Norregaard PK, Hogberg T (2004) 4-Acylamino-and 4-ureidobenzamides as melanin-concentrating hormone (MCH) receptor 1 antagonists. Bioorg Med Chem Lett 14(20):5075–5080. PubMedCrossRefGoogle Scholar
  79. 79.
    Kratochwil NA, Malherbe P, Lindemann L, Ebeling M, Hoener MC, Muhlemann A, Porter RH, Stahl M, Gerber PR (2005) An automated system for the analysis of G protein-coupled receptor transmembrane binding pockets: alignment, receptor-based pharmacophores, and their application. J Chem Inf Model 45(5):1324–1336. PubMedCrossRefGoogle Scholar
  80. 80.
    Malherbe P, Kratochwil N, Muhlemann A, Zenner MT, Fischer C, Stahl M, Gerber PR, Jaeschke G, Porter RH (2006) Comparison of the binding pockets of two chemically unrelated allosteric antagonists of the mGlu5 receptor and identification of crucial residues involved in the inverse agonism of MPEP. J Neurochem 98(2):601–615. PubMedCrossRefGoogle Scholar
  81. 81.
    Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318(5854):1258–1265. PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330(6007):1091–1095. PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Chrencik JE, Roth CB, Terakado M, Kurata H, Omi R, Kihara Y, Warshaviak D, Nakade S, Asmar-Rovira G, Mileni M, Mizuno H, Griffith MT, Rodgers C, Han GW, Velasquez J, Chun J, Stevens RC, Hanson MA (2015) Crystal structure of antagonist bound human Lysophosphatidic acid receptor 1. Cell 161(7):1633–1643. PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Christopher JA, Brown J, Dore AS, Errey JC, Koglin M, Marshall FH, Myszka DG, Rich RL, Tate CG, Tehan B, Warne T, Congreve M (2013) Biophysical fragment screening of the beta1-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design. J Med Chem 56(9):3446–3455. PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Congreve M, Andrews SP, Dore AS, Hollenstein K, Hurrell E, Langmead CJ, Mason JS, Ng IW, Tehan B, Zhukov A, Weir M, Marshall FH (2012) Discovery of 1,2,4-triazine derivatives as adenosine a(2A) antagonists using structure based drug design. J Med Chem 55(5):1898–1903. PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Dore AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B, Hurrell E, Bennett K, Congreve M, Magnani F, Tate CG, Weir M, Marshall FH (2011) Structure of the adenosine a(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure 19(9):1283–1293. PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Fenalti G, Zatsepin NA, Betti C, Giguere P, Han GW, Ishchenko A, Liu W, Guillemyn K, Zhang H, James D, Wang D, Weierstall U, Spence JC, Boutet S, Messerschmidt M, Williams GJ, Gati C, Yefanov OM, White TA, Oberthuer D, Metz M, Yoon CH, Barty A, Chapman HN, Basu S, Coe J, Conrad CE, Fromme R, Fromme P, Tourwe D, Schiller PW, Roth BL, Ballet S, Katritch V, Stevens RC, Cherezov V (2015) Structural basis for bifunctional peptide recognition at human delta-opioid receptor. Nat Struct Mol Biol 22(3):265–268. PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Glukhova A, Thal DM, Nguyen AT, Vecchio EA, Jorg M, Scammells PJ, May LT, Sexton PM, Christopoulos A (2017) Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 168(5):867–877.e813. PubMedCrossRefGoogle Scholar
  89. 89.
    Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK (2012) Structure of the delta-opioid receptor bound to naltrindole. Nature 485(7398):400–404. PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi T (2012) Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482(7386):547–551. PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, Velasquez J, Kuhn P, Stevens RC (2008) A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 16(6):897–905. PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335(6070):851–855. PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, Zhao S, Shui W, Li S, Korde A, Laprairie RB, Stahl EL, Ho JH, Zvonok N, Zhou H, Kufareva I, Wu B, Zhao Q, Hanson MA, Bohn LM, Makriyannis A, Stevens RC, Liu ZJ (2016) Crystal structure of the human cannabinoid receptor CB1. Cell 167(3):750–762.e714. PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling RC, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK (2015) Structural insights into micro-opioid receptor activation. Nature 524(7565):315–321. PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC (2008) The 2.6 Angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322(5905):1211–1217. PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM, Rosemond E, Green HF, Liu T, Chae PS, Dror RO, Shaw DE, Weis WI, Wess J, Kobilka BK (2012) Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482(7386):552–556. PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hubner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504(7478):101–106. PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Lebon G, Edwards PC, Leslie AG, Tate CG (2015) Molecular determinants of CGS21680 binding to the human adenosine A2A receptor. Mol Pharmacol 87(6):907–915. PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lebon G, Warne T, Edwards PC, Bennett K, Langmead CJ, Leslie AG, Tate CG (2011) Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 474(7352):521–525. PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S (2012) Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 485(7398):321–326. PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Miller RL, Thompson AA, Trapella C, Guerrini R, Malfacini D, Patel N, Han GW, Cherezov V, Calo G, Katritch V, Stevens RC (2015) The importance of ligand-receptor conformational pairs in stabilization: spotlight on the N/OFQ G protein-coupled receptor. Structure 23(12):2291–2299. PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Moukhametzianov R, Warne T, Edwards PC, Serrano-Vega MJ, Leslie AG, Tate CG, Schertler GF (2011) Two distinct conformations of helix 6 observed in antagonist-bound structures of a beta1-adrenergic receptor. Proc Natl Acad Sci U S A 108(20):8228–8232. PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Oswald C, Rappas M, Kean J, Dore AS, Errey JC, Bennett K, Deflorian F, Christopher JA, Jazayeri A, Mason JS, Congreve M, Cooke RM, Marshall FH (2016) Intracellular allosteric antagonism of the CCR9 receptor. Nature 540(7633):462–465. PubMedCrossRefGoogle Scholar
  104. 104.
    Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilka BK (2013) Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody. Nature 502(7472):575–579. PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, Rasmussen SG, Choi HJ, Devree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK (2011) Structure and function of an irreversible agonist-beta(2) adrenoceptor complex. Nature 469(7329):236–240. PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Sato T, Baker J, Warne T, Brown GA, Leslie AG, Congreve M, Tate CG (2015) Pharmacological analysis and structure determination of 7-Methylcyanopindolol-bound beta1-adrenergic receptor. Mol Pharmacol 88(6):1024–1034. PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Segala E, Guo D, Cheng RK, Bortolato A, Deflorian F, Dore AS, Errey JC, Heitman LH, Ijzerman AP, Marshall FH, Cooke RM (2016) Controlling the dissociation of ligands from the adenosine A2A receptor through modulation of salt bridge strength. J Med Chem 59(13):6470–6479. PubMedCrossRefGoogle Scholar
  108. 108.
    Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, Rosenbaum DM (2016) High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature.
  109. 109.
    Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J, Jennings A, Okada K (2014) High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513(7516):124–127. PubMedCrossRefGoogle Scholar
  110. 110.
    Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Li J, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B (2013) Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341(6152):1387–1390. PubMedCrossRefGoogle Scholar
  111. 111.
    Thal DM, Sun B, Feng D, Nawaratne V, Leach K, Felder CC, Bures MG, Evans DA, Weis WI, Bachhawat P, Kobilka TS, Sexton PM, Kobilka BK, Christopoulos A (2016) Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 531(7594):335–340. PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC (2012) Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature 485(7398):395–399. PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Thorsen TS, Matt R, Weis WI, Kobilka BK (2014) Modified T4 lysozyme fusion proteins facilitate G protein-coupled receptor crystallogenesis. Structure 22(11):1657–1664. PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Wacker D, Fenalti G, Brown MA, Katritch V, Abagyan R, Cherezov V, Stevens RC (2010) Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography. J Am Chem Soc 132(33):11443–11445. PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL (2017) Crystal structure of an LSD-bound human serotonin receptor. Cell 168(3):377–389. e312. PubMedCrossRefGoogle Scholar
  116. 116.
    Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou XE, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, HE X (2013) Structural basis for molecular recognition at serotonin receptors. Science 340(6132):610–614. PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Warne T, Edwards PC, Leslie AG, Tate CG (2012) Crystal structures of a stabilized beta1-adrenoceptor bound to the biased agonists bucindolol and carvedilol. Structure 20(5):841–849. PubMedCrossRefGoogle Scholar
  118. 118.
    Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AG, Tate CG, Schertler GF (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454(7203):486–491. PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Weichert D, Kruse AC, Manglik A, Hiller C, Zhang C, Hubner H, Kobilka BK, Gmeiner P (2014) Covalent agonists for studying G protein-coupled receptor activation. Proc Natl Acad Sci U S A 111(29):10744–10748. PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012) Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485(7398):327–332. PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC (2011) Structure of an agonist-bound human A2A adenosine receptor. Science 332(6027):322–327. PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Yin J, Babaoglu K, Brautigam CA, Clark L, Shao Z, Scheuermann TH, Harrell CM, Gotter AL, Roecker AJ, Winrow CJ, Renger JJ, Coleman PJ, Rosenbaum DM (2016) Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat Struct Mol Biol 23(4):293–299. PubMedCrossRefGoogle Scholar
  123. 123.
    Yin J, Mobarec JC, Kolb P, Rosenbaum DM (2015) Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. Nature 519(7542):247–250. PubMedCrossRefGoogle Scholar
  124. 124.
    Zhang C, Srinivasan Y, Arlow DH, Fung JJ, Palmer D, Zheng Y, Green HF, Pandey A, Dror RO, Shaw DE, Weis WI, Coughlin SR, Kobilka BK (2012) High-resolution crystal structure of human protease-activated receptor 1. Nature 492(7429):387–392. PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Zhang D, Gao ZG, Zhang K, Kiselev E, Crane S, Wang J, Paoletta S, Yi C, Ma L, Zhang W, Han GW, Liu H, Cherezov V, Katritch V, Jiang H, Stevens RC, Jacobson KA, Zhao Q, Wu B (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 520(7547):317–321. PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Zhang J, Zhang K, Gao ZG, Paoletta S, Zhang D, Han GW, Li T, Ma L, Zhang W, Muller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q (2014) Agonist-bound structure of the human P2Y12 receptor. Nature 509(7498):119–122. PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W, Fenalti G, Zhang W, Muller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509(7498):115–118. PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Liu X, Ahn S, Kahsai AW, Meng KC, Latorraca NR, Pani B, Venkatakrishnan AJ, Masoudi A, Weis W, Dror RO, Chen X, Lefkowitz RJ, Kobilka BK (2017) Mechanism of intracellular allosteric β 2AR antagonist revealed by X-ray crystal structure. Nature 548(7668):480–484. PubMedCrossRefGoogle Scholar
  129. 129.
    Cheng RKY, Fiez-Vandal C, Schlenker O, Edman K, Aggeler B, Brown DG, Brown GA, Cooke RM, Dumelin CE, Doré AS, Geschwindner S, Grebner C, Hermansson NO, Jazayeri A, Johansson P, Leong L, Prihandoko R, Rappas M, Soutter H, Snijder A, Sundström L, Tehan B, Thornton P, Troast D, Wiggin G, Zhukov A, Marshall FH, Dekker N (2017) Structural insight into allosteric modulation of proteaseactivated receptor 2. Nature 545(7652):112–115. PubMedCrossRefGoogle Scholar
  130. 130.
    Lu J, Byrne N, Wang J, Bricogne G, Brown FK, Chobanian HR, Colletti SL, Di Salvo J, Thomas-Fowlkes B, Guo Y, Hall DL, Hadix J, Hastings NB, Hermes JD, Ho T, Howard AD, Josien H, Kornienko M, Lumb KJ, Miller MW, Patel SB, Pio B, Plummer CW, Sherborne BS, Sheth P, Souza S, Tummala S, Vonrhein C, Webb M, Allen SJ, Johnston JM, Weinglass AB, Sharma S, Soisson SM (2017) Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol 24(7):570–577. PubMedCrossRefGoogle Scholar
  131. 131.
    Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, Pu M, Korde A, Jiang S, Ho JH, Han GW, Ding K, Li X, Liu H, Hanson MA, Zhao S, Bohn LM, Makriyannis A, Stevens RC, Liu ZJ (2017) Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 547(7664):468–471. PubMedCrossRefGoogle Scholar
  132. 132.
    Shihoya W, Nishizawa T, Yamashita K, Inoue A, Hirata K, Kadji FMN, Okuta A, Tani K, Aoki J, Fujiyoshi Y, Doi T, Nureki O (2017) X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. Nat Struct Mol Biol 24(9):758–764. PubMedCrossRefGoogle Scholar
  133. 133.
    Zhang H, Han GW, Batyuk A, Ishchenko A, White KL, Patel N, Sadybekov A, Zamlynny B, Rudd MT, Hollenstein K, Tolstikova A, White TA, Hunter MS, Weierstall U, Liu W, Babaoglu K, Moore EL, Katz RD, Shipman JM, Garcia-Calvo M, Sharma S, Sheth P, Soisson SM, Stevens RC, Katritch V, Cherezov V (2017) Structural basis for selectivity and diversity in angiotensin II receptors. Nature 544(7650):327–332. PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Zhang H, Qiao A, Yang D, Yang L, Dai A, de Graaf C, Reedtz-Runge S, Dharmarajan V, Zhang H, Han GW, Grant TD, Sierra RG, Weierstall U, Nelson G, Liu W, Wu Y, Ma L, Cai X, Lin G, Wu X, Geng Z, Dong Y, Song G, Griffin PR, Lau J, Cherezov V, Yang H, Hanson MA, Stevens RC, Zhao Q, Jiang H, Wang MW, Wu B (2017) Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 546(7657):259–264. PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S, Liu K, Cai X, Dai A, Lin G, Liu D, Wu F, Wu Y, Zhao S, Ye L, Han GW, Lau J, Wu B, Hanson MA, Liu ZJ, Wang MW, Stevens RC (2017) Human GLP- 1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 546(7657):312–315. PubMedCrossRefGoogle Scholar
  136. 136.
    Surgand JS, Rodrigo J, Kellenberger E, Rognan D (2006) A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Proteins 62(2):509–538. PubMedCrossRefGoogle Scholar
  137. 137.
    Weill N, Rognan D (2009) Development and validation of a novel protein-ligand fingerprint to mine chemogenomic space: application to G protein-coupled receptors and their ligands. J Chem Inf Model 49(4):1049–1062. PubMedCrossRefGoogle Scholar
  138. 138.
    Nohr AC, Shehata MA, Hauser AS, Isberg V, Mokrosinski J, Andersen KB, Farooqi IS, Pedersen DS, Gloriam DE, Brauner-Osborne H (2017) The orphan G protein-coupled receptor GPR139 is activated by the peptides: adrenocorticotropic hormone (ACTH), alpha-, and beta-melanocyte stimulating hormone (alpha-MSH, and beta-MSH), and the conserved core motif HFRW. Neurochem Int 102:105–113. PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Wellendorph P, Hansen KB, Balsgaard A, Greenwood JR, Egebjerg J, Brauner-Osborne H (2005) Deorphanization of GPRC6A: a promiscuous L-alpha-amino acid receptor with preference for basic amino acids. Mol Pharmacol 67(3):589–597. PubMedCrossRefGoogle Scholar
  140. 140.
    Faure H, Gorojankina T, Rice N, Dauban P, Dodd RH, Brauner-Osborne H, Rognan D, Ruat M (2009) Molecular determinants of non-competitive antagonist binding to the mouse GPRC6A receptor. Cell Calcium 46(5–6):323–332. PubMedCrossRefGoogle Scholar
  141. 141.
    Gloriam DE, Wellendorph P, Johansen LD, Thomsen AR, Phonekeo K, Pedersen DS, Brauner-Osborne H (2011) Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor. Chem Biol 18(11):1489–1498. PubMedCrossRefGoogle Scholar
  142. 142.
    van der Horst E, Peironcely JE, Ijzerman AP, Beukers MW, Lane JR, van Vlijmen HW, Emmerich MT, Okuno Y, Bender A (2010) A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization. BMC Bioinformatics 11:316. PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Bento AP, Gaulton A, Hersey A, Bellis LJ, Chambers J, Davies M, Kruger FA, Light Y, Mak L, McGlinchey S, Nowotka M, Papadatos G, Santos R, Overington JP (2014) The ChEMBL bioactivity database: an update. Nucleic Acids Res 42(Database issue):D1083–D1090. PubMedCrossRefGoogle Scholar
  144. 144.
    Okuno Y, Tamon A, Yabuuchi H, Niijima S, Minowa Y, Tonomura K, Kunimoto R, Feng C (2008) GLIDA: GPCR – ligand database for chemical genomics drug discovery – database and tools update. Nucleic Acids Res 36(Database issue):D907–D912. PubMedGoogle Scholar
  145. 145.
    Roth BL, Lopez E, Beischel S, Westkaemper RB, Evans JM (2004) Screening the receptorome to discover the molecular targets for plant-derived psychoactive compounds: a novel approach for CNS drug discovery. Pharmacol Ther 102(2):99–110. PubMedCrossRefGoogle Scholar
  146. 146.
    Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK (2007) Relating protein pharmacology by ligand chemistry. Nat Biotechnol 25(2):197–206. PubMedCrossRefGoogle Scholar
  147. 147.
    Lin H, Sassano MF, Roth BL, Shoichet BK (2013) A pharmacological organization of G protein-coupled receptors. Nat Methods 10(2):140–146. PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Ngo T, Ilatovskiy AV, Stewart AG, Coleman JL, McRobb FM, Riek RP, Graham RM, Abagyan R, Kufareva I, Smith NJ (2017) Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat Chem Biol 13(2):235–242. PubMedCrossRefGoogle Scholar
  149. 149.
    The UniProt C (2017) UniProt: the universal protein knowledgebase. Nucleic Acids Res 45(D1):D158–D169. CrossRefGoogle Scholar
  150. 150.
    Yates A, Akanni W, Amode MR, Barrell D, Billis K, Carvalho-Silva D, Cummins C, Clapham P, Fitzgerald S, Gil L, Giron CG, Gordon L, Hourlier T, Hunt SE, Janacek SH, Johnson N, Juettemann T, Keenan S, Lavidas I, Martin FJ, Maurel T, McLaren W, Murphy DN, Nag R, Nuhn M, Parker A, Patricio M, Pignatelli M, Rahtz M, Riat HS, Sheppard D, Taylor K, Thormann A, Vullo A, Wilder SP, Zadissa A, Birney E, Harrow J, Muffato M, Perry E, Ruffier M, Spudich G, Trevanion SJ, Cunningham F, Aken BL, Zerbino DR, Flicek P (2016) Ensembl 2016. Nucleic Acids Res 44(D1):D710–D716. PubMedCrossRefGoogle Scholar
  151. 151.
    Sanders MP, Fleuren WW, Verhoeven S, van den Beld S, Alkema W, de Vlieg J, Klomp JP (2011) ss-TEA: entropy based identification of receptor specific ligand binding residues from a multiple sequence alignment of class a GPCRs. BMC Bioinformatics 12:332. PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Sanders MP, Verhoeven S, de Graaf C, Roumen L, Vroling B, Nabuurs SB, de Vlieg J, Klomp JP (2011) Snooker: a structure-based pharmacophore generation tool applied to class a GPCRs. J Chem Inf Model 51(9):2277–2292. PubMedCrossRefGoogle Scholar
  153. 153.
    Sanders MP, Roumen L, van der Horst E, Lane JR, Vischer HF, van Offenbeek J, de Vries H, Verhoeven S, Chow KY, Verkaar F, Beukers MW, McGuire R, Leurs R, Ijzerman AP, de Vlieg J, de Esch IJ, Zaman GJ, Klomp JP, Bender A, de Graaf C (2012) A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design. J Med Chem 55(11):5311–5325. PubMedCrossRefGoogle Scholar
  154. 154.
    Roland WS, Sanders MP, van Buren L, Gouka RJ, Gruppen H, Vincken JP, Ritschel T (2015) Snooker structure-based pharmacophore model explains differences in agonist and blocker binding to bitter receptor hTAS2R39. PLoS One 10(3):e0118200. PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Klabunde T, Giegerich C, Evers A (2009) Sequence-derived three-dimensional pharmacophore models for G-protein-coupled receptors and their application in virtual screening. J Med Chem 52(9):2923–2932. PubMedCrossRefGoogle Scholar
  156. 156.
    Fidom K, Isberg V, Hauser AS, Mordalski S, Lehto T, Bojarski AJ, Gloriam DE (2015) A new crystal structure fragment-based pharmacophore method for G protein-coupled receptors. Methods 71:104–112. PubMedCrossRefGoogle Scholar
  157. 157.
    Frandsen IO, Boesgaard MW, Fidom K, Hauser AS, Isberg V, Bräuner-Osborne H, Wellendorph P, Gloriam DE (2017) Identification of Histamine H3 Receptor Ligands Using a New Crystal Structure Fragmentbased Method. Sci Rep. 7(1):4829. PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Wichard JD, Ter Laak A, Krause G, Heinrich N, Kuhne R, Kleinau G (2011) Chemogenomic analysis of G-protein coupled receptors and their ligands deciphers locks and keys governing diverse aspects of signalling. PLoS One 6(2):e16811. PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Kooistra AJ, Leurs R, de Esch IJ, de Graaf C (2015) Structure-based prediction of G-protein-coupled receptor ligand function: a beta-adrenoceptor case study. J Chem Inf Model 55(5):1045–1061. PubMedCrossRefGoogle Scholar
  160. 160.
    Kooistra AJ, Vischer HF, McNaught-Flores D, Leurs R, de Esch IJ, de Graaf C (2016) Function-specific virtual screening for GPCR ligands using a combined scoring method. Sci Rep 6:28288. PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Yang D, de Graaf C, Yang L, Song G, Dai A, Cai X, Feng Y, Reedtz-Runge S, Hanson MA, Yang H, Jiang H, Stevens RC, Wang MW (2016) Structural determinants of binding the seven-transmembrane domain of the glucagon-like Peptide-1 receptor (GLP-1R). J Biol Chem 291(25):12991–13004. PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Harpsoe K, Isberg V, Tehan BG, Weiss D, Arsova A, Marshall FH, Brauner-Osborne H, Gloriam DE (2015) Selective negative allosteric modulation of metabotropic glutamate receptors - a structural perspective of ligands and mutants. Sci Rep 5:13869. PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Berman HM, JW ZF, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Wilkinson MD, Dumontier M, Aalbersberg IJ, Appleton G, Axton M, Baak A, Blomberg N, Boiten JW, da Silva Santos LB, Bourne PE, Bouwman J, Brookes AJ, Clark T, Crosas M, Dillo I, Dumon O, Edmunds S, Evelo CT, Finkers R, Gonzalez-Beltran A, Gray AJ, Groth P, Goble C, Grethe JS, Heringa J, t Hoen PA, Hooft R, Kuhn T, Kok R, Kok J, Lusher SJ, Martone ME, Mons A, Packer AL, Persson B, Rocca-Serra P, Roos M, van Schaik R, Sansone SA, Schultes E, Sengstag T, Slater T, Strawn G, Swertz MA, Thompson M, van der Lei J, van Mulligen E, Velterop J, Waagmeester A, Wittenburg P, Wolstencroft K, Zhao J, Mons B (2016) The FAIR guiding principles for scientific data management and stewardship. Sci Data 3:160018. PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Márton Vass
    • 1
  • Albert J. Kooistra
    • 1
    • 2
  • Stefan Verhoeven
    • 3
  • David Gloriam
    • 4
  • Iwan J. P. de Esch
    • 1
  • Chris de Graaf
    • 1
  1. 1.Department of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and SystemsVrije Universiteit AmsterdamAmsterdamThe Netherlands
  2. 2.Centre for Molecular and Biomolecular Informatics (CMBI)Radboud University Medical CenterNijmegenThe Netherlands
  3. 3.Netherlands eScience CenterAmsterdamThe Netherlands
  4. 4.Department of Drug Design and PharmacologyUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations