Conformational Ensemble View of G Protein-Coupled Receptors and the Effect of Mutations and Ligand Binding
Abstract
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.
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.Additional details
- Eprint ID
- 36618
- Resolver ID
- CaltechAUTHORS:20130128-104922610
- 5R21MH073910
- NIH
- PharmSelex
- Caltech Materials and Process Simulation Center (MSC)
- Created
-
2013-01-28Created from EPrint's datestamp field
- Updated
-
2021-11-09Created from EPrint's last_modified field
- Series Name
- Methods in Enzymology
- Series Volume or Issue Number
- 520