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Molecular basis for high-affinity agonist binding in GPCRs.

Warne T, Edwards PC, Doré AS, Leslie AGW, Tate CG
Science 364 775-778 (2019)
Related entries: 6h7l, 6h7m, 6h7o

Cited: 71 times
EuropePMC logo PMID: 31072904

Abstract

G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists as compared with when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of β1AR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.

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  6. Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands. Scarano N, Espinoza S, Brullo C, Cichero E. Int J Mol Sci 25 8226 (2024)

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  1. Structure determination of GPCRs: cryo-EM compared with X-ray crystallography. García-Nafría J, Tate CG. Biochem Soc Trans 49 2345-2355 (2021)
  2. Structural insights into melatonin receptors. Stauch B, Johansson LC, Cherezov V. FEBS J 287 1496-1510 (2020)
  3. Allosteric communication regulates ligand-specific GPCR activity. Ma N, Nivedha AK, Vaidehi N. FEBS J 288 2502-2512 (2021)
  4. Easily Established and Multifunctional Synthetic Nanobody Libraries as Research Tools. Liu B, Yang D. Int J Mol Sci 23 1482 (2022)
  5. Single Domain Antibody application in bacterial infection diagnosis and neutralization. Qin Q, Liu H, He W, Guo Y, Zhang J, She J, Zheng F, Zhang S, Muyldermans S, Wen Y. Front Immunol 13 1014377 (2022)
  6. Structural Insights into Ligand-Receptor Interactions Involved in Biased Agonism of G-Protein Coupled Receptors. Jóźwiak K, Płazińska A. Molecules 26 851 (2021)
  7. Purinergic GPCR transmembrane residues involved in ligand recognition and dimerization. Salmaso V, Jain S, Jacobson KA. Methods Cell Biol 166 133-159 (2021)
  8. Finding the Perfect Fit: Conformational Biosensors to Determine the Efficacy of GPCR Ligands. Olson KM, Campbell A, Alt A, Traynor JR. ACS Pharmacol Transl Sci 5 694-709 (2022)
  9. Intracellular VHHs to monitor and modulate GPCR signaling. Raynaud P, Gauthier C, Jugnarain V, Jean-Alphonse F, Reiter E, Bruneau G, Crépieux P. Front Endocrinol (Lausanne) 13 1048601 (2022)
  10. Structures of Adrenoceptors. Helfinger L, Tate CG. Handb Exp Pharmacol 285 13-26 (2024)
  11. The Impact of Nanobodies on G Protein-Coupled Receptor Structural Biology and Their Potential as Therapeutic Agents. Salom D, Wu A, Liu CC, Palczewski K. Mol Pharmacol 106 155-163 (2024)

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