Cited by 1,227Receptor Mechanisms and SignalingProtein Kinase Regulation and GTPase SignalingNeuroscience and Neuropharmacology Research

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The Molecular Basis of G Protein–Coupled Receptor Activation

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Weis, William I., Kobilka, Brian K.·2018·Annual Review of Biochemistry

DOI 10.1146/annurev-biochem-060614-033910PMC PMC6535337

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Abstract

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.

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Authors: Weis, W. I., & Kobilka, B. K.
Affiliations: Stanford Medicine (US)
Corresponding author: Kobilka, Brian K.
ORCID: Weis, William I.
Kobilka, Brian K.
Venue: Annual Review of Biochemistry
Publisher: Annual Reviews
Published: 2018-06-20
Volume: 87
Issue: 1
Pages: 897-919
ISSN: 0066-4154 (ISSN-L)
1545-4509
DOI: 10.1146/annurev-biochem-060614-033910
PMC: PMC6535337
OpenAlex: W2809303314
Cited by: 1,227
References: 72
Citations by year: 2026: 160 · 2025: 191 · 2024: 183 · 2023: 174 · 2022: 151 · 2021: 161 · 2020: 124 · 2019: 71 · 2018: 11
FWCI: 9.03
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Annual Review of Biochemistry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute of General Medical Sciences (R01GM083118)
National Institute of Neurological Disorders and Stroke (R01NS028471)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: G protein-coupled receptors, G protein activation, GTPase activity, arrestin, allosteric communication, receptor conformational change, ligand efficacy, GPCR pharmacology, G protein dissociation
MeSH terms: Allosteric Regulation, Binding Sites, Energy Metabolism, Humans, Ligands, Models, Molecular, Protein Conformation, Conserved Sequence, Crystallography, X-Ray, Receptors, G-Protein-Coupled

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The Molecular Basis of G Protein–Coupled Receptor Activation

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