GPCR activation mechanisms across classes and macro/microscales

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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.

Original languageEnglish
JournalNature Structural and Molecular Biology
Issue number11
Pages (from-to)879-888
Publication statusPublished - 2021

Bibliographical note

Funding Information:
This work was supported by the Lundbeck Foundation (grants R163-2013-16327 and R218-2016-1266), the

Funding Information:
Novo Nordisk Foundation (grant NNF18OC0031226) and Independent Research Fund Denmark | Natural

Funding Information:
Sciences (grant 8021-00173B) to D.E.G and by the American Lebanese Syrian Associated Charities (ALSAC).

Publisher Copyright:
© 2021, The Author(s).

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