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Trends Biochem Sci. 2014 May;39(5):233-44. doi: 10.1016/j.tibs.2014.03.002. Epub 2014 Apr 21.

Allosteric sodium in class A GPCR signaling.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: katritch@scripps.edu.
2
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3
National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27599, USA.

Abstract

Despite their functional and structural diversity, G-protein-coupled receptors (GPCRs) share a common mechanism of signal transduction via conformational changes in the seven-transmembrane (7TM) helical domain. New major insights into this mechanism come from the recent crystallographic discoveries of a partially hydrated sodium ion that is specifically bound in the middle of the 7TM bundle of multiple class A GPCRs. This review discusses the remarkable structural conservation and distinct features of the Na(+) pocket in this most populous GPCR class, as well as the conformational collapse of the pocket upon receptor activation. New insights help to explain allosteric effects of sodium on GPCR agonist binding and activation, and sodium's role as a potential co-factor in class A GPCR function.

KEYWORDS:

GPCR activation; allosteric modulation; biased signaling; conserved pocket; sodium ion; water binding

PMID:
24767681
PMCID:
PMC4106411
DOI:
10.1016/j.tibs.2014.03.002
[Indexed for MEDLINE]
Free PMC Article
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