Journal
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 87
Volume 87, Issue -, Pages 897-919Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-biochem-060614-033910
Keywords
7-TM receptors; G protein-coupled receptor; GPCR; beta(2)-adrenergic receptor; allostery; energy landscape
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Funding
- NIGMS NIH HHS [R01 GM083118] Funding Source: Medline
- NINDS NIH HHS [R01 NS028471] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM083118] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS028471] Funding Source: NIH RePORTER
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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 alpha and beta gamma 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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