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Evolving cryo-EM structural approaches for GPCR drug discovery.

Zhang X, Johnson RM, Drulyte I, Yu L, Kotecha A, Danev R, Wootten D, Sexton PM, Belousoff MJ
Structure 29 963-974.e6 (2021)
Related entries: 7lcj, 7lck

Cited: 18 times
EuropePMC logo PMID: 33957078

Abstract

G protein-coupled receptors (GPCRs) are the largest class of cell surface drug targets. Advances in stabilization of GPCR:transducer complexes, together with improvements in cryoelectron microscopy (cryo-EM) have recently been applied to structure-assisted drug design for GPCR agonists. Nonetheless, limitations in the commercial application of these approaches, including the use of nanobody 35 (Nb35) to aid complex stabilization and the high cost of 300 kV imaging, have restricted broad application of cryo-EM in drug discovery. Here, using the PF 06882961-bound GLP-1R as exemplar, we validated the formation of stable complexes with a modified Gs protein in the absence of Nb35. In parallel, we compare 200 versus 300 kV image acquisition using a Falcon 4 or K3 direct electron detector. Moreover, the 200 kV Glacios-Falcon 4 yielded a 3.2 Å map with clear density for bound drug and multiple structurally ordered waters. Our work paves the way for broader commercial application of cryo-EM for GPCR drug discovery.

Reviews - 7lci mentioned but not cited (2)

  1. Evolving Experimental Techniques for Structure-Based Drug Design. Aplin C, Milano SK, Zielinski KA, Pollack L, Cerione RA. J Phys Chem B 126 6599-6607 (2022)
  2. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)

Articles - 7lci mentioned but not cited (6)

  1. The Novel Application of Geometric Morphometrics with Principal Component Analysis to Existing G Protein-Coupled Receptor (GPCR) Structures. Wiseman DN, Samra N, Román Lara MM, Penrice SC, Goddard AD. Pharmaceuticals (Basel) 14 953 (2021)
  2. An automated pipeline integrating AlphaFold 2 and MODELLER for protein structure prediction. Gil Zuluaga FH, D'Arminio N, Bardozzo F, Tagliaferri R, Marabotti A. Comput Struct Biotechnol J 21 5620-5629 (2023)
  3. Improved AlphaFold modeling with implicit experimental information. Terwilliger TC, Poon BK, Afonine PV, Schlicksup CJ, Croll TI, Millán C, Richardson JS, Read RJ, Adams PD. Nat Methods 19 1376-1382 (2022)
  4. New Insights into the Structure and Function of Class B1 GPCRs. Cary BP, Zhang X, Cao J, Johnson RM, Piper SJ, Gerrard EJ, Wootten D, Sexton PM. Endocr Rev 44 492-517 (2023)
  5. Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps. Alshammari M, Wriggers W, Sun J, He J. QRB Discov 3 e16 (2022)
  6. Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR. Wang H, Hu W, Xu T, Yuan Y, Liu D, Wüthrich K. iScience 26 106918 (2023)


Reviews citing this publication (4)

  1. Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors. Lu J, Piper SJ, Zhao P, Miller LJ, Wootten D, Sexton PM. Int J Mol Sci 23 8069 (2022)
  2. Applications and prospects of cryo-EM in drug discovery. Zhu KF, Yuan C, Du YM, Sun KL, Zhang XK, Vogel H, Jia XD, Gao YZ, Zhang QF, Wang DP, Zhang HW. Mil Med Res 10 10 (2023)
  3. Developing novel antifungals: lessons from G protein-coupled receptors. Velazhahan V, McCann BL, Bignell E, Tate CG. Trends Pharmacol Sci 44 162-174 (2023)
  4. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)

Articles citing this publication (6)

  1. Conserved class B GPCR activation by a biased intracellular agonist. Zhao LH, He Q, Yuan Q, Gu Y, He X, Shan H, Li J, Wang K, Li Y, Hu W, Wu K, Shen J, Xu HE. Nature 621 635-641 (2023)
  2. Characterizing conformational states in GPCR structures using machine learning. Buyanov I, Popov P. Sci Rep 14 1098 (2024)
  3. Drug-Targeted Genomes: Mutability of Ion Channels and GPCRs. Raines R, McKnight I, White H, Legg K, Lee C, Li W, Lee PHU, Shim JW. Biomedicines 10 594 (2022)
  4. Routine sub-2.5 Å cryo-EM structure determination of GPCRs. Danev R, Belousoff M, Liang YL, Zhang X, Eisenstein F, Wootten D, Sexton PM. Nat Commun 12 4333 (2021)
  5. Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations. Höring C, Conrad M, Söldner CA, Wang J, Sticht H, Strasser A, Miao Y. Int J Mol Sci 22 10047 (2021)
  6. Yeast-based directed-evolution for high-throughput structural stabilization of G protein-coupled receptors (GPCRs). Meltzer M, Zvagelsky T, Hadad U, Papo N, Engel S. Sci Rep 12 8657 (2022)


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