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Conformational Ensemble View of G Protein-Coupled Receptors and the Effect of Mutations and Ligand Binding

Abrol, Ravinder and Kim, Soo-Kyung and Bray, Jenelle K. and Trzaskowski, Bartosz and Goddard, William A., III (2013) Conformational Ensemble View of G Protein-Coupled Receptors and the Effect of Mutations and Ligand Binding. In: G Protein Coupled Receptors — Structure. Methods in Enzymology. No.520. Academic Press , Oxford, pp. 31-48. ISBN 9780123918611.

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G protein-coupled receptors (GPCRs) are integral membrane proteins that can convert an extracellular signal into multiple intracellular signaling processes. This pleiotropy of GPCRs is enabled by their structural flexibility manifested in thermally accessible multiple conformations, each of which may be capable of activating a different signaling cascade inside the cell (Kenakin & Miller, 2010). Different subsets of conformations can be potentially stabilized through mutations, or binding to various ligands (inverse agonists, antagonists, and agonists), or binding to G proteins, etc. Structure determination efforts have led to a small subset of these receptors being crystallized in one or two distinct conformations, but computational methods can predict an ensemble of conformations that characterize the full thermodynamic landscape of the receptor. Mutations in the receptor or binding of ligands can modulate this energy landscape, by stabilizing a unique set of conformations under different conditions, which may correspond to a specific downstream physiological function. These studies can provide testable hypotheses on the structural basis of GPCR activation and functional selectivity.

Item Type:Book Section
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URLURL TypeDescription
Abrol, Ravinder0000-0001-7333-6793
Kim, Soo-Kyung0000-0002-4498-5441
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2013 Elsevier Inc. This work was supported in part by the NIH Grant 5R21MH073910, by funding from PharmSelex, and by gifts to the Materials and Process Simulation Center at Caltech.
Funding AgencyGrant Number
Caltech Materials and Process Simulation Center (MSC)UNSPECIFIED
Subject Keywords:GPCRs; Seven-transmembrane receptors; Protein structure prediction; Mutagenesis; Functional selectivity; Conformational energy landscape
Series Name:Methods in Enzymology
Issue or Number:520
Record Number:CaltechAUTHORS:20130128-104922610
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Official Citation:Ravinder Abrol, Soo-Kyung Kim, Jenelle K. Bray, Bartosz Trzaskowski, William A. Goddard III, Chapter Two - Conformational Ensemble View of G Protein-Coupled Receptors and the Effect of Mutations and Ligand Binding, In: P. Michael Conn, Editor(s), Methods in Enzymology, Academic Press, 2013, Volume 520, Pages 31-48, ISSN 0076-6879, ISBN 9780123918611, 10.1016/B978-0-12-391861-1.00002-2.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36618
Deposited On:28 Jan 2013 23:50
Last Modified:09 Nov 2021 23:23

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