Publication — IRIC

GPCR activation mechanisms across classes and macro/microscales.

Two-thirds of human hormones and one-third of clinical drugs activate ~350 G-protein-coupled receptors (GPCR) belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes, which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here we show that, although they use the same structural scaffold and share several ‘helix macroswitches’, the GPCR classes differ in their ‘residue microswitch’ positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and methods for contact analysis applicable for any functional determinants. This provides a superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins, laying the foundation for receptor-function studies and drugs with the desired modality.

Date de publication
1er novembre 2021
Hauser AS, Kooistra AJ, Munk C, Heydenreich FM, Veprintsev DB, Bouvier M, Babu MM, Gloriam DE
Référence PubMed
Nat Struct Mol Biol 2021;28(11):879-888
ID PubMed
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.