The Molecular Basis of G Protein–Coupled Receptor Activation
By William I. Weis, Brian K. Kobilka. 2018
1,047 citations recorded by the source corpus.
G protein–coupled receptors (GPCRs) mediate the majority of cellular responses to external stimuli. Upon activation by a ligand, the receptor binds to a partner heterotrimeric G protein and promotes exchange of GTP for GDP, leading to dissociation of the G protein into α and βγ subunits that mediate downstream signals. GPCRs can also activate distinct signaling pathways through arrestins. Active states of GPCRs form by small rearrangements of the ligand-binding, or orthosteric, site that are amplified into larger conformational changes. Molecular understanding of the allosteric coupling between ligand binding and G protein or arrestin interaction is emerging from structures of several GPCRs crystallized in inactive and active states, spectroscopic data, and computer simulations. The coupling is loose, rather than concerted, and agonist binding does not fully stabilize the receptor in an active conformation. Distinct intermediates whose populations are shifted by ligands of different efficacies underlie the complex pharmacology of GPCRs.
Subfields: Cellular and Molecular Neuroscience, Computational Theory and Mathematics, Molecular Biology
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Citations in the corpus
- FGF/FGFR signaling in health and disease (2020, background): “Structurally, GPCRs are composed of an N-terminal extracellular domain, seventransmembrane helices, and a C-terminal region.(60) A growing number of studies have revealed that various members of GPCRs and receptor tyrosine kinase (RTKs) can form heterocomplexes together and trigger different intrace”
- Structure and dynamics of the CGRP receptor in apo and peptide-bound forms (2021, result): “Nonetheless, the proposed model of class B1 GPCR activation is consistent with the observations for other classes of GPCRs, including the more extensively studied class A GPCRs, where biophysical studies have demonstrated that the binding of agonist or G protein alone is insufficient to recapitulate”