Skip to main content

Advertisement

SpringerLink
Log in

The impact of structural biology in medicine illustrated with four case studies

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The contributions of structural biology to drug discovery have expanded over the last 20 years from structure-based ligand optimization to a broad range of clinically relevant topics including the understanding of disease, target discovery, screening for new types of ligands, discovery of new modes of action, addressing clinical challenges such as side effects or resistance, and providing data to support drug registration. This expansion of scope is due to breakthroughs in the technology, which allow structural information to be obtained rapidly and for more complex molecular systems, but also due to the combination of different technologies such as X-ray, NMR, and other biophysical methods, which allows one to get a more complete molecular understanding of disease and ways to treat it. In this review, we provide examples of the types of impact molecular structure information can have in the clinic for both low molecular weight and biologic drug discovery and describe several case studies from our own work to illustrate some of these contributions.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Berman HM, Bhat TN, Bourne PE, Feng Z, Gilliland G, Weissig H, Westbrook J (2000) The protein data Bank and the challenge of structural genomics. Nat Struct Biol 7(Suppl):957–959

    Article  CAS  PubMed  Google Scholar 

  2. Ostrem JM, Shokat KM (2016) Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov 15:771–785

    Article  CAS  PubMed  Google Scholar 

  3. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Donegan RK, Hill SE, Freeman DM, Nguyen E, Orwig SD, Turnage KC, Lieberman RL (2015) Structural basis for misfolding in myocilin-associated glaucoma. Hum Mol Genet 24:2111–2124

    Article  CAS  PubMed  Google Scholar 

  5. Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov 15:533–550

    Article  CAS  PubMed  Google Scholar 

  6. Petzold G, Fischer ES, Thoma NH (2016) Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4 (CRBN) ubiquitin ligase. Nature 532:127–130

    Article  CAS  PubMed  Google Scholar 

  7. Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H (2016) Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov 15:605–619

    Article  CAS  PubMed  Google Scholar 

  8. van Montfort RL, Workman P (2009) Structure-based design of molecular cancer therapeutics. Trends Biotechnol 27:315–328

    Article  PubMed  Google Scholar 

  9. Huggins DJ, Sherman W, Tidor B (2012) Rational approaches to improving selectivity in drug design. J Med Chem 55:1424–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sanderson K (2013) Irreversible kinase inhibitors gain traction. Nat Rev Drug Discov 12:649–651

    Article  CAS  PubMed  Google Scholar 

  11. Shokat K, Velleca M (2002) Novel chemical genetic approaches to the discovery of signal transduction inhibitors. Drug Discov Today 7:872–879

    Article  CAS  PubMed  Google Scholar 

  12. Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, Antonakos B, Chen CH, Chen Z, Cooke VG et al (2016) Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535:148–152

    Article  CAS  PubMed  Google Scholar 

  13. Stoll F, Goller AH, Hillisch A (2011) Utility of protein structures in overcoming ADMET-related issues of drug-like compounds. Drug Discov Today 16:530–538

    Article  CAS  PubMed  Google Scholar 

  14. Kurt Yilmaz N, Swanstrom R, Schiffer CA (2016) Improving viral protease inhibitors to counter drug resistance. Trends Microbiol 24:547–557

    Article  CAS  PubMed  Google Scholar 

  15. Lahti JL, Tang GW, Capriotti E, Liu T, Altman RB (2012) Bioinformatics and variability in drug response: a protein structural perspective. J R Soc Interface 9:1409–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–502

    Article  CAS  PubMed  Google Scholar 

  17. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880

    Article  CAS  PubMed  Google Scholar 

  18. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, Taylor K, Herrmann R, Seymour JF, Arthur C et al (2003) Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102:276–283

    Article  CAS  PubMed  Google Scholar 

  19. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U et al (2002) Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16:2190–2196

    Article  CAS  PubMed  Google Scholar 

  20. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289:1938–1942

    Article  CAS  PubMed  Google Scholar 

  21. Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 62:4236–4243

    CAS  PubMed  Google Scholar 

  22. Cowan-Jacob SW, Guez V, Fendrich G, Griffin JD, Fabbro D, Furet P, Liebetanz J, Mestan J, Manley PW (2004) Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem 4:285–299

    Article  CAS  PubMed  Google Scholar 

  23. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E et al (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129–141

    Article  CAS  PubMed  Google Scholar 

  24. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O’Brien SG, Litzow M et al (2007) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110:3540–3546

    Article  CAS  PubMed  Google Scholar 

  25. Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW (2007) Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr 63:80–93

    Article  CAS  PubMed  Google Scholar 

  26. Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S et al (2010) Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-y l)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 53:4701–4719

    Article  CAS  PubMed  Google Scholar 

  27. Nagar B, Hantschel O, Young MA, Scheffzek K, Veach D, Bornmann W, Clarkson B, Superti-Furga G, Kuriyan J (2003) Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112:859–871

    Article  CAS  PubMed  Google Scholar 

  28. Adrian FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley P et al (2006) Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol 2:95–102

    Article  CAS  PubMed  Google Scholar 

  29. Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F et al (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463:501–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J et al (2010) Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J Am Chem Soc 132:7043–7048

    Article  CAS  PubMed  Google Scholar 

  31. Wylie A, Schoepfer J, Berellini G, Cai H, Caravatti G, Cotesta S, Dodd S, Donovan J, Erb B, Furet P et al (2014) ABL001, a potent allosteric inhibitor of BCR-ABL, prevents emergence of resistant disease when administered in combination with Nilotinib in an in vivo murine model of chronic myeloid leukemia. Blood 124:398

    Google Scholar 

  32. Wylie AA, Schoepfer J, Jahnke W, Cowan-Jacob SW, Loo A, Furet P, Marzinzik AL, Pelle X, Donovan J, Zhu W et al (2017) The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature 543:733–737

    Article  CAS  PubMed  Google Scholar 

  33. Hughes TP, Goh Y-T, Ottmann OG, Minami H, Rea D, Lang F, Mauro MJ, DeAngelo DJ, Talpaz M, Hochhaus A et al (2016) Expanded phase 1 study of ABL001, a potent, allosteric inhibitor of BCR-ABL, reveals significant and durable responses in patients with CML-chronic phase with failure of prior TKI therapy. Blood 128:625

    Article  Google Scholar 

  34. Bhang HE, Ruddy DA, Krishnamurthy Radhakrishna V, Caushi JX, Zhao R, Hims MM, Singh AP, Kao I, Rakiec D, Shaw P et al (2015) Studying clonal dynamics in response to cancer therapy using high-complexity barcoding. Nat Med 21:440–448

    Article  CAS  PubMed  Google Scholar 

  35. Chan RJ, Feng GS (2007) PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 109:862–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Grossmann KS, Rosario M, Birchmeier C, Birchmeier W (2010) The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res 106:53–89

    Article  CAS  PubMed  Google Scholar 

  37. Prahallad A, Heynen GJ, Germano G, Willems SM, Evers B, Vecchione L, Gambino V, Lieftink C, Beijersbergen RL, Di Nicolantonio F et al (2015) PTPN11 is a central node in intrinsic and acquired resistance to targeted cancer drugs. Cell Rep 12:1978–1985

    Article  CAS  PubMed  Google Scholar 

  38. Scott LM, Chen L, Daniel KG, Brooks WH, Guida WC, Lawrence HR, Sebti SM, Lawrence NJ, Wu J (2011) Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs. Bioorg Med Chem Lett 21:730–733

    Article  CAS  PubMed  Google Scholar 

  39. Grosskopf S, Eckert C, Arkona C, Radetzki S, Bohm K, Heinemann U, Wolber G, von Kries JP, Birchmeier W, Rademann J (2015) Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem 10:815–826

    Article  CAS  PubMed  Google Scholar 

  40. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE (1998) Crystal structure of the tyrosine phosphatase SHP-2. Cell 92:441–450

    Article  CAS  PubMed  Google Scholar 

  41. Sugimoto S, Wandless TJ, Shoelson SE, Neel BG, Walsh CT (1994) Activation of the SH2-containing protein tyrosine phosphatase, SH-PTP2, by phosphotyrosine-containing peptides derived from insulin receptor substrate-1. J Biol Chem 269:13614–13622

    CAS  PubMed  Google Scholar 

  42. Pluskey S, Wandless TJ, Walsh CT, Shoelson SE (1995) Potent stimulation of SH-PTP2 phosphatase activity by simultaneous occupancy of both SH2 domains. J Biol Chem 270:2897–2900

    Article  PubMed  Google Scholar 

  43. Garcia Fortanet J, Chen CH, Chen YN, Chen Z, Deng Z, Firestone B, Fekkes P, Fodor M, Fortin PD, Fridrich C et al (2016) Allosteric inhibition of SHP2: Identification of a potent, selective, and orally efficacious phosphatase inhibitor. J Med Chem 59:7773–7782

    Article  CAS  PubMed  Google Scholar 

  44. Yu ZH, Xu J, Walls CD, Chen L, Zhang S, Zhang R, Wu L, Wang L, Liu S, Zhang ZY (2013) Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations. J Biol Chem 288:10472–10482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. LaRochelle JR, Fodor M, Xu X, Durzynska I, Fan L, Stams T, Chan HM, LaMarche MJ, Chopra R, Wang P et al (2016) Structural and functional consequences of three cancer-associated mutations of the oncogenic phosphatase SHP2. Biochemistry 55:2269–2277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mullard A (2016) 2015 FDA drug approvals. Nat Rev Drug Discov 15:73–76

    Article  CAS  PubMed  Google Scholar 

  47. Zhang YJ, Luo L, Desai DD (2016) Overview on biotherapeutic proteins: impact on bioanalysis. Bioanalysis 8:1–9

    Article  PubMed  Google Scholar 

  48. Gilliland GL, Luo J, Vafa O, Almagro JC (2012) Leveraging SBDD in protein therapeutic development: antibody engineering. Methods Mol Biol 841:321–349

    Article  CAS  PubMed  Google Scholar 

  49. Robinson LN, Tharakaraman K, Rowley KJ, Costa VV, Chan KR, Wong YH, Ong LC, Tan HC, Koch T, Cain D et al (2015) Structure-guided Design of an Anti-dengue Antibody Directed to a non-immunodominant epitope. Cell 162:493–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Burton DR, Hangartner L (2016) Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu Rev Immunol 34:635–659

    Article  CAS  PubMed  Google Scholar 

  51. Kwiatkowski W, Gray PC, Choe S (2014) Engineering TGF-beta superfamily ligands for clinical applications. Trends Pharmacol Sci 35:648–657

    Article  CAS  PubMed  Google Scholar 

  52. Lewis SM, Wu X, Pustilnik A, Sereno A, Huang F, Rick HL, Guntas G, Leaver-Fay A, Smith EM, Ho C et al (2014) Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat Biotechnol 32:191–198

    Article  CAS  PubMed  Google Scholar 

  53. Wang RE, Wang Y, Zhang Y, Gabrelow C, Zhang Y, Chi V, Fu Q, Luo X, Wang D, Joseph S et al (2016) Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant. Proc Natl Acad Sci U S A 113:11501–11506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lawrence PB, Price JL (2016) How PEGylation influences protein conformational stability. Curr Opin Chem Biol 34:88–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gilbreth RN, Chacko BM, Grinberg L, Swers JS, Baca M (2014) Stabilization of the third fibronectin type III domain of human tenascin-C through minimal mutation and rational design. Protein Eng Des Sel 27:411–418

    Article  CAS  PubMed  Google Scholar 

  56. Apgar JR, Mader M, Agostinelli R, Benard S, Bialek P, Johnson M, Gao Y, Krebs M, Owens J, Parris K et al (2016) Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody. MAbs 8:1302–1318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brader ML, Baker EN, Dunn MF, Laue TM, Carpenter JF (2017) Using X-ray crystallography to simplify and accelerate biologics drug development. J Pharm Sci 106:477–494

    Article  CAS  PubMed  Google Scholar 

  58. Weatherill EE, Cain KL, Heywood SP, Compson JE, Heads JT, Adams R, Humphreys DP (2012) Towards a universal disulphide stabilised single chain Fv format: importance of interchain disulphide bond location and vL-vH orientation. Protein Eng Des Sel 25:321–329

    Article  CAS  PubMed  Google Scholar 

  59. Lehmann A, Wixted JH, Shapovalov MV, Roder H, Dunbrack RL Jr, Robinson MK (2015) Stability engineering of anti-EGFR scFv antibodies by rational design of a lambda-to-kappa swap of the VL framework using a structure-guided approach. MAbs 7:1058–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gresl T, Storz U, Sandercock C (2016) An update on obtaining and enforcing therapeutic antibody patent claims. Nat Biotechnol 34:1242–1244

    Article  CAS  PubMed  Google Scholar 

  61. Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, Sineshchekova O, Saxena P, Sutton CR, Chen D et al (2013) An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res 73:6024–6035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Manglik A, Kobilka BK, Steyaert J (2017) Nanobodies to study G protein-coupled receptor structure and function. Annu Rev Pharmacol Toxicol 57:19–37

    Article  CAS  PubMed  Google Scholar 

  63. Bernasconi-Elias P, Hu T, Jenkins D, Firestone B, Gans S, Kurth E, Capodieci P, Deplazes-Lauber J, Petropoulos K, Thiel P et al (2016) Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35:6077–6086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mallon DH, Bradley JA, Taylor CJ, Kosmoliaptsis V (2014) Structural and electrostatic analysis of HLA B-cell epitopes: inference on immunogenicity and prediction of humoral alloresponses. Curr Opin Organ Transplant 19:420–427

    Article  CAS  PubMed  Google Scholar 

  65. Pomes A, Chruszcz M, Gustchina A, Minor W, Mueller GA, Pedersen LC, Wlodawer A, Chapman MD (2015) 100 years later: Celebrating the contributions of x-ray crystallography to allergy and clinical immunology. J Allergy Clin Immunol 136(29–37):e10

    Google Scholar 

  66. Gala K, Chandarlapaty S (2014) Molecular pathways: HER3 targeted therapy. Clin Cancer Res 20:1410–1416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang N, Chang Y, Rios A, An Z (2016) HER3/ErbB3, an emerging cancer therapeutic target. Acta Biochim Biophys Sin Shanghai 48:39–48

    PubMed  Google Scholar 

  68. Arteaga CL, Engelman JA (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25:282–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dawson JP, Bu Z, Lemmon MA (2007) Ligand-induced structural transitions in ErbB receptor extracellular domains. Structure 15:942–954

    Article  CAS  PubMed  Google Scholar 

  70. Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S (2003) An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 12:541–552

    Article  CAS  PubMed  Google Scholar 

  71. Liu P, Cleveland TE, Bouyain S, Byrne PO, Longo PA, Leahy DJ (2012) A single ligand is sufficient to activate EGFR dimers. Proc Natl Acad Sci U S A 109:10861–10866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang X, Rickert M, Garcia KC (2005) Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science 310:1159–1163

    Article  CAS  PubMed  Google Scholar 

  73. Arenas-Ramirez N, Zou C, Popp S, Zingg D, Brannetti B, Wirth E, Calzascia T, Kovarik J, Sommer L, Zenke G et al (2016) Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2. Sci Transl Med 8:367ra166

    Article  PubMed  Google Scholar 

  74. Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, Moustafa Z, Thomas RK, Greulich H, Schinzel A et al (2010) An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17:298–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wilson TR, Lee DY, Berry L, Shames DS, Settleman J (2011) Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell 20:158–172

    Article  CAS  PubMed  Google Scholar 

  76. Mukherjee A, Badal Y, Nguyen XT, Miller J, Chenna A, Tahir H, Newton A, Parry G, Williams S (2011) Profiling the HER3/PI3K pathway in breast tumors using proximity-directed assays identifies correlations between protein complexes and phosphoproteins. PLoS One 6:e16443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM (2005) Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7:301–311

    Article  CAS  PubMed  Google Scholar 

  78. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317–328

    Article  CAS  PubMed  Google Scholar 

  79. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, Leahy DJ (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421:756–760

    Article  CAS  PubMed  Google Scholar 

  80. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116

    Article  CAS  PubMed  Google Scholar 

  81. Boyman O, Sprent J (2012) The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12:180–190

    Article  CAS  PubMed  Google Scholar 

  82. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, Moraga I, Raeber ME, Bowman GR, Novick P et al (2012) Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 484:529–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Subramaniam S, Earl LA, Falconieri V, Milne JL, Egelman EH (2016) Resolution advances in cryo-EM enable application to drug discovery. Curr Opin Struct Biol 41:194–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Tehan BG, Christopher JA (2016) The use of conformationally thermostabilised GPCRs in drug discovery: application to fragment, structure and biophysical techniques. Curr Opin Pharmacol 30:8–13

    Article  CAS  PubMed  Google Scholar 

  85. Christopher JA, Aves SJ, Bennett KA, Dore AS, Errey JC, Jazayeri A, Marshall FH, Okrasa K, Serrano-Vega MJ, Tehan BG et al (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 58:6653–6664

    Article  CAS  PubMed  Google Scholar 

  86. Biankin AV, Piantadosi S, Hollingsworth SJ (2015) Patient-centric trials for therapeutic development in precision oncology. Nature 526:361–370

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA

    Tiancen Hu, Elizabeth R. Sprague, Michelle Fodor, Travis Stams & Kirk L. Clark

  2. Novartis Institutes for Biomedical Research, 4002, Basel, Switzerland

    Sandra W. Cowan-Jacob

Authors
  1. Tiancen Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth R. Sprague
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michelle Fodor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Travis Stams
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kirk L. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra W. Cowan-Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandra W. Cowan-Jacob.

Ethics declarations

Disclosure

The authors are all employees of Novartis (Novartis Institute for Biomedical Research, Inc. TH, ES, MF, TS and KC, and Novartis Pharma AG. SWCJ)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, T., Sprague, E.R., Fodor, M. et al. The impact of structural biology in medicine illustrated with four case studies. J Mol Med 96, 9–19 (2018). https://doi.org/10.1007/s00109-017-1565-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-017-1565-x

Keywords

Search

Navigation