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Structural insight into apelin receptor-G protein stoichiometry.

Yue Y, Liu L, Wu LJ, Wu Y, Wang L, Li F, Liu J, Han GW, Chen B, Lin X, Brouillette RL, Breault É, Longpré JM, Shi S, Lei H, Sarret P, Stevens RC, Hanson MA, Xu F
Nat Struct Mol Biol 29 688-697 (2022)
Related entries: 7sus, 7w0l, 7w0m, 7w0n, 7w0p

Cited: 5 times
EuropePMC logo PMID: 35817871

Abstract

The technique of cryogenic-electron microscopy (cryo-EM) has revolutionized the field of membrane protein structure and function with a focus on the dominantly observed molecular species. This report describes the structural characterization of a fully active human apelin receptor (APJR) complexed with heterotrimeric G protein observed in both 2:1 and 1:1 stoichiometric ratios. We use cryo-EM single-particle analysis to determine the structural details of both species from the same sample preparation. Protein preparations, in the presence of the endogenous peptide ligand ELA or a synthetic small molecule, both demonstrate these mixed stoichiometric states. Structural differences in G protein engagement between dimeric and monomeric APJR suggest a role for the stoichiometry of G protein-coupled receptor- (GPCR-)G protein coupling on downstream signaling and receptor pharmacology. Furthermore, a small, hydrophobic dimer interface provides a starting framework for additional class A GPCR dimerization studies. Together, these findings uncover a mechanism of versatile regulation through oligomerization by which GPCRs can modulate their signaling.

Reviews citing this publication (2)

  1. New insights into GPCR coupling and dimerisation from cryo-EM structures. Gusach A, García-Nafría J, Tate CG. Curr Opin Struct Biol 80 102574 (2023)
  2. Neuroprotection afforded by targeting G protein-coupled receptors in heteromers and by heteromer-selective drugs. Franco R, Navarro G. Front Pharmacol 14 1222158 (2023)

Articles citing this publication (3)

  1. Conformational Dynamics of the Activated GLP-1 Receptor-Gs Complex Revealed by Cross-Linking Mass Spectrometry and Integrative Structure Modeling. Yuan S, Xia L, Wang C, Wu F, Zhang B, Pan C, Fan Z, Lei X, Stevens RC, Sali A, Sun L, Shui W. ACS Cent Sci 9 992-1007 (2023)
  2. Expanding the apelin receptor pharmacological toolbox using novel fluorescent ligands. Williams TL, Macrae RGC, Kuc RE, Brown AJH, Maguire JJ, Davenport AP. Front Endocrinol (Lausanne) 14 1139121 (2023)
  3. The activation mechanism and antibody binding mode for orphan GPR20. Lin X, Jiang S, Wu Y, Wei X, Han GW, Wu L, Liu J, Chen B, Zhang Z, Zhao S, Cherezov V, Xu F. Cell Discov 9 23 (2023)


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