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Cell. 2013 Dec 5;155(6):1258-69. doi: 10.1016/j.cell.2013.11.008. Epub 2013 Nov 27.

Genetically encoded chemical probes in cells reveal the binding path of urocortin-I to CRF class B GPCR.

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1
Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Abstract

Molecular determinants regulating the activation of class B G-protein-coupled receptors (GPCRs) by native peptide agonists are largely unknown. We have investigated here the interaction between the corticotropin releasing factor receptor type 1 (CRF1R) and its native 40-mer peptide ligand Urocortin-I directly in mammalian cells. By incorporating unnatural amino acid photochemical and new click-chemical probes into the intact receptor expressed in the native membrane of live cells, 44 intermolecular spatial constraints have been derived for the ligand-receptor interaction. The data were analyzed in the context of the recently resolved crystal structure of CRF1R transmembrane domain and existing extracellular domain structures, yielding a complete conformational model for the peptide-receptor complex. Structural features of the receptor-ligand complex yield molecular insights on the mechanism of receptor activation and the basis for discrimination between agonist and antagonist function.

PMID:
24290358
PMCID:
PMC3916339
DOI:
10.1016/j.cell.2013.11.008
[Indexed for MEDLINE]
Free PMC Article
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