Skip to main content

Advertisement

Springer Nature Link
Log in

Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Metabotropic glutamate receptors (mGluR) are mainly expressed in the central nervous system (CNS) and contain eight receptor subtypes, named mGluR1 to mGluR8. The crystal structures of mGluR1 and mGluR5 that are bound with the negative allosteric modulator (NAM) were reported recently. These structures provide a basic model for all class C of G-protein coupled receptors (GPCRs) and may aid in the design of new allosteric modulators for the treatment of CNS disorders. However, these structures are only combined with NAMs in the previous reports. The conformations that are bound with positive allosteric modulator (PAM) or agonist of mGluR1/5 remain unknown. Moreover, the structural information of the other six mGluRs and the comparisons of the mGluRs family have not been explored in terms of their binding pockets, the binding modes of different compounds, and important binding residues. With these crystal structures as the starting point, we built 3D structural models for six mGluRs by using homology modeling and molecular dynamics (MD) simulations. We systematically compared their allosteric binding sites/pockets, the important residues, and the selective residues by using a series of comparable dockings with both the NAM and the PAM. Our results show that several residues played important roles for the receptors’ selectivity. The observations of detailed interactions between compounds and their correspondent receptors are congruent with the specificity and potency of derivatives or compounds bioassayed in vitro. We then carried out 100 ns MD simulations of mGluR5 (residue 26-832, formed by Venus Flytrap domain, a so-called cysteine-rich domain, and 7 trans-membrane domains) bound with antagonist/NAM and with agonist/PAM. Our results show that both the NAM and the PAM seemed stable in class C GPCRs during the MD. However, the movements of “ionic lock,” of trans-membrane domains, and of some activation-related residues in 7 trans-membrane domains of mGluR5 were congruent with the findings in class A GPCRs. Finally, we selected nine representative bound structures to perform 30 ns MD simulations for validating the stabilities of interactions, respectively. All these bound structures kept stable during the MD simulations, indicating that the binding poses in this present work are reasonable. We provided new insight into better understanding of the structural and functional roles of the mGluRs family and facilitated the future structure-based design of novel ligands of mGluRs family with therapeutic potential.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
€32.70 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Finland)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51:7–62.

    CAS  PubMed  Google Scholar 

  2. Sugiyama H, Ito I, Hirono C. A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature. 1987;325:531–3.

    Article  CAS  PubMed  Google Scholar 

  3. Mølck C, Harpsøe K, Gloriam DE, Mathiesen JM, Nielsen SM, Bräuner-Osborne H. mGluR5: exploration of orthosteric and allosteric ligand binding pockets and their applications to drug discovery. Neurochem Res. 2014;39:1–14.

    Article  Google Scholar 

  4. Gregory KJ, Dong EN, Meiler J, Conn PJ. Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology. 2011;60:66–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Niswender CM, Conn PJ. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol. 2010;50:295.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Nicoletti F, Bockaert J, Collingridge G, Conn P, Ferraguti F, Schoepp D, et al. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology. 2011;60:1017–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Ferraguti F, Shigemoto R. Metabotropic glutamate receptors. Cell Tissue Res. 2006;326:483–504.

    Article  CAS  PubMed  Google Scholar 

  8. Conn PJ, Lindsley CW, Meiler J, Niswender CM. Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov. 2014;13:692–708.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Brauner-Osborne H, Wellendorph P, Jensen AA. Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Curr Drug Targets. 2007;8:169–84.

    Article  PubMed  Google Scholar 

  10. Flor PJ, Acher FC. Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochem Pharmacol. 2012;84:414–24.

    Article  CAS  PubMed  Google Scholar 

  11. Pin J-P, Galvez T, Prézeau L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther. 2003;98:325–54.

    Article  CAS  PubMed  Google Scholar 

  12. Dalton J, Gómez-Santacana X, Llebaria A, Giraldo J. A computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (in) activation. J Chem Inf Model. 2014;54:1476–87.

    Article  CAS  PubMed  Google Scholar 

  13. Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature. 2000;407:971–7.

    Article  CAS  PubMed  Google Scholar 

  14. Muto T, Tsuchiya D, Morikawa K, Jingami H. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 2007;104:3759–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Kniazeff J, Prézeau L, Rondard P, Pin J-P, Goudet C. Dimers and beyond: the functional puzzles of class C GPCRs. Pharmacol Ther. 2011;130:9–25.

    Article  CAS  PubMed  Google Scholar 

  16. Wellendorph P, Bräuner‐Osborne H. Molecular basis for amino acid sensing by family CG‐protein‐coupled receptors. Br J Pharmacol. 2009;156:869–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Feng Z, Alqarni MH, Yang P, Tong Q, Chowdhury A, Wang L, et al. Modeling, molecular dynamics simulation and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs. J Chem Inf Model. 2014;54:2483–99.

    Article  CAS  PubMed  Google Scholar 

  18. Goudet C, Vilar B, Courtiol T, Deltheil T, Bessiron T, Brabet I, et al. A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB J. 2012;26:1682–93.

    Article  CAS  PubMed  Google Scholar 

  19. Burford NT, Watson J, Bertekap R, Alt A. Strategies for the identification of allosteric modulators of G-protein-coupled receptors. Biochem Pharmacol. 2011;81:691–702.

    Article  CAS  PubMed  Google Scholar 

  20. Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009;8:41–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Emmitte KA. mGlu5 negative allosteric modulators: a patent review (2010–2012). Expert Opin Ther Pat. 2013;23:393–408.

    Article  CAS  PubMed  Google Scholar 

  22. Rocher J-P, Bonnet B, Bolea C, Lutjens R, Le Poul E, Poli S, et al. mGluR5 negative allosteric modulators overview: a medicinal chemistry approach towards a series of novel therapeutic agents. Curr Top Med Chem. 2011;11:680–95.

    Article  CAS  PubMed  Google Scholar 

  23. Lavreysen H, Langlois X, Ahnaou A, Drinkenburg W, te Riele P, Biesmans I, et al. Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H] JNJ-40068782. J Pharmacol Exp Ther. 2013;346:514–27.

    Article  CAS  PubMed  Google Scholar 

  24. Hopkins CR. Is there a path forward for mGlu2 positive allosteric modulators for the treatment of schizophrenia? ACS Chem Neurosci. 2013;4:211–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Macdonald GJ, Lindsley CW. A unique industrial–academic collaboration towards the next generation of schizophrenia therapeutics. Curr Top Med Chem. 2014;14:304–12.

    Article  CAS  PubMed  Google Scholar 

  26. Lindsley CW, Hopkins CR. Metabotropic glutamate receptor 4 (mGlu4)-positive allosteric modulators for the treatment of Parkinson’s disease: historical perspective and review of the patent literature. Expert Opin Ther Pat. 2012;22:461–81.

    Article  CAS  PubMed  Google Scholar 

  27. Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014;344:58–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Doré AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, et al. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature. 2014;511:557–62.

    Article  PubMed  Google Scholar 

  29. SYBYL-X 1.3, Tripos International, 1699 South Hanley Rd., St. Louis, MO, 63144, USA. 2010.

  30. Martí-Renom MA, Stuart AC, Fiser A, Sánchez R, Melo F, Šali A. Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol. 2000;29:291–325.

    Article  Google Scholar 

  31. Xie XQ, Chen JZ, Billings EM. 3D structural model of the G‐protein‐coupled cannabinoid CB2 receptor. Proteins Struct Funct Bioinf. 2003;53:307–19.

    Article  CAS  Google Scholar 

  32. Wiederstein M, Sippl MJ. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007;35:W407–10.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr. 1993;26:283–91.

    Article  CAS  Google Scholar 

  34. Lovell SC, Davis IW, Arendall WB, de Bakker PI, Word JM, Prisant MG, et al. Structure validation by Cα geometry: ϕ, ψ and Cβ deviation. Proteins. 2003;50:437–50.

    Article  CAS  PubMed  Google Scholar 

  35. Jain AN. Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities. J Comput Aided Mol Des. 1996;10:427–40.

    Article  CAS  PubMed  Google Scholar 

  36. Chen J-Z, Wang J, Xie X-Q. GPCR structure-based virtual screening approach for CB2 antagonist search. J Chem Inf Model. 2007;47:1626–37.

    Article  CAS  PubMed  Google Scholar 

  37. Søndergaard CR, Olsson MH, Rostkowski M, Jensen JH. Improved treatment of ligands and coupling effects in empirical calculation and rationalization of p K a values. J Chem Theory Comput. 2011;7:2284–95.

    Article  Google Scholar 

  38. Pedretti A, Villa L, Vistoli G. VEGA: a versatile program to convert, handle and visualize molecular structure on Windows-based PCs. J Mol Graph Model. 2002;21:47–9.

    Article  CAS  PubMed  Google Scholar 

  39. Hsin J, Arkhipov A, Yin Y, Stone JE, Schulten K. Using VMD: an introductory tutorial. Curr Protoc Bioinformatics. 2008; 5.7. 1-5.7. 48.

  40. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79:926.

    Article  CAS  Google Scholar 

  41. Kalé L, Skeel R, Bhandarkar M, Brunner R, Gursoy A, Krawetz N, et al. NAMD2: greater scalability for parallel molecular dynamics. J Comput Phys. 1999;151:283–312.

    Article  Google Scholar 

  42. Brooks BR, Bruccoleri RE, Olafson BD. CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem. 1983;4:187–217.

    Article  CAS  Google Scholar 

  43. MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B. 1998;102:3586–616.

    Article  CAS  PubMed  Google Scholar 

  44. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG. A smooth particle mesh Ewald method. J Chem Phys. 1995;103:8577–93.

    Article  CAS  Google Scholar 

  45. Feng Z, Hou T, Li Y. Studies on the interactions between β2 adrenergic receptor and Gs protein by molecular dynamics simulations. J Chem Inf Model. 2012;52:1005–14.

    Article  CAS  PubMed  Google Scholar 

  46. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, et al. Crystal structure of rhodopsin: AG protein-coupled receptor. Science. 2000;289:739–45.

    Article  CAS  PubMed  Google Scholar 

  47. Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science. 2010;330:1091–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Hollenstein K, Kean J, Bortolato A, Cheng RK, Doré AS, Jazayeri A, et al. Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature. 2013;499:438–43.

    Article  CAS  PubMed  Google Scholar 

  49. Wang C, Wu H, Katritch V, Han GW, Huang X-P, Liu W, et al. Structure of the human smoothened receptor bound to an antitumour agent. Nature. 2013;497:338–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Kohara A, Takahashi M, Yatsugi S-i, Tamura S, Shitaka Y, Hayashibe S, et al. Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models. Brain Res. 2008;1191:168–79.

    Article  CAS  PubMed  Google Scholar 

  51. Kohara A, Nagakura Y, Kiso T, Toya T, Watabiki T, Tamura S, et al. Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models. Eur J Pharmacol. 2007;571:8–16.

    Article  CAS  PubMed  Google Scholar 

  52. Pałucha A, Brański P, Szewczyk B, Wierońska JM, Kłak K, Pilc A. Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist. Pharmacol Biochem Behav. 2005;81:901–6.

    Article  PubMed  Google Scholar 

  53. Turlington M, Noetzel MJ, Chun A, Zhou Y, Gogliotti RD, Nguyen ED, et al. Exploration of allosteric agonism structure–activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl) ethynyl)-N-(3-methyloxetan-3-yl) picolinamide (ML254). J Med Chem. 2013;56:7976–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Lindsley CW, Wisnoski DD, Leister WH, O’Brien JA, Lemaire W, Williams DL, et al. Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1, 3-diphenyl-1 H-pyrazol-5-yl) benzamides that potentiate receptor function in vivo. J Med Chem. 2004;47:5825–8.

    Article  CAS  PubMed  Google Scholar 

  55. Bridges TM, Rook JM, Noetzel MJ, Morrison RD, Zhou Y, Gogliotti RD, et al. Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. Drug Metab Dispos. 2013;41:1703–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Pomierny-Chamioło L, Rup K, Pomierny B, Niedzielska E, Kalivas PW, Filip M. Metabotropic glutamatergic receptors and their ligands in drug addiction. Pharmacol Ther. 2014;142:281–305.

    Article  PubMed  Google Scholar 

  57. Dhanya R-P, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, et al. Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats. J Med Chem. 2010;54:342–53.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Woltering TJ, Wichmann J, Goetschi E, Knoflach F, Ballard TM, Huwyler J, et al. Synthesis and characterization of 1, 3-dihydro-benzo[1, 4] diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists. Bioorg Med Chem Lett. 2010;20:6969–74.

    Article  CAS  PubMed  Google Scholar 

  59. Mølck C, Harpsøe K, Gloriam DE, Clausen RP, Madsen U, Pedersen LØ, et al. Pharmacological characterization and modeling of the binding sites of novel 1, 3-bis (pyridinylethynyl) benzenes as metabotropic glutamate receptor 5-selective negative allosteric modulators. Mol Pharmacol. 2012;82:929–37.

    Article  PubMed  Google Scholar 

  60. Gregory KJ, Nguyen ED, Reiff SD, Squire EF, Stauffer SR, Lindsley CW, et al. Probing the metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a “molecular switch” in PAM pharmacology. Mol Pharmacol. 2013;83:991–1006.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Vinson PN, Conn PJ. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology. 2012;62:1461–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Matosin N, Fernandez-Enright F, Frank E, Deng C, Wong J, Huang X-F, et al. Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics. J Psychiatry Neurosci. 2014;39:407.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Lundström L, Bissantz C, Beck J, Wettstein J, Woltering T, Wichmann J, et al. Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators. Br J Pharmacol. 2011;164:521–37.

    Article  PubMed Central  PubMed  Google Scholar 

  64. Rovira X, Malhaire F, Scholler P, Rodrigo J, Gonzalez-Bulnes P, Llebaria A, Pin J-P, Giraldo J, Goudet C. Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors. FASEB J. 2014;29:116–130.

  65. Doherty A, Palmer M, Bortolotto Z, Hargreaves A, Kingston A, Ornstein P, et al. A novel, competitive mGlu5 receptor antagonist (LY344545) blocks DHPG‐induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices. Br J Pharmacol. 2000;131:239–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Feng Z, Hou T, Li Y. Selectivity and activation of dopamine D3R from molecular dynamics. J Mol Model. 2012;18:5051–63.

    Article  CAS  PubMed  Google Scholar 

  67. Feng Z, Hou T, Li Y. Docking and MD study of histamine H4R based on the crystal structure of H1R. J Mol Graph Model. 2013;39:1–12.

    Article  CAS  PubMed  Google Scholar 

  68. Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, et al. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature. 2011;477:549–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The project is supported by funding from the NIDA P30DA035778A1 and NIH R01DA025612.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Zhiwei Feng, Shifan Ma, Guanxing Hu & Xiang-Qun Xie

  2. NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Zhiwei Feng, Shifan Ma, Guanxing Hu & Xiang-Qun Xie

  3. Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Zhiwei Feng, Shifan Ma, Guanxing Hu & Xiang-Qun Xie

  4. Departments of Computational Biology and of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA

    Xiang-Qun Xie

Authors
  1. Zhiwei Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shifan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guanxing Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiang-Qun Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiang-Qun Xie.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

Figure S1 shows the sequence alignments among mGluRs family. Figure S2 shows the comparisons of the crystal structure between mGluR1 and mGluR5. Figure S3 shows the Ramachandran plots of other six mGluRs, including mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, and mGluR8. Figure S4 shows the common 3D structure of mGluRs family. Figure S5 shows the comparisons of the NAM between mGluR1 and mGluR5. Figure S6 shows the superposition and comparison of mGluR5 (class C) with D3R (class A), CRF1R (class B), and SMO receptor (class F). Figure S7 shows the structural information of compounds discussed in the present work. Figure S8 shows the comparisons of binding mode of MTEP and MPEP in mGluR5. Figure S9 shows the comparisons of mGluR5 bound with different compounds during 100 ns MD simulation. Figure S10 shows conformational changes (view from extracellular side) of 7TMD bound with different compounds after 100 ns MD simulation. Figure S11 shows the alignments of other nine complexes between before-MD and after-MD. Table S1 shows sequence identities of six subtypes with two group I mGluRs (mGluR1 and mGluR5). This material is available free of charge via the Internet at http://www.aaps.org. (DOCX 13644 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, Z., Ma, S., Hu, G. et al. Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family. AAPS J 17, 737–753 (2015). https://doi.org/10.1208/s12248-015-9742-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-015-9742-8

KEY WORDS

Search

Navigation