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Linking agonist binding to histamine H1 receptor activation.

Authors :
Jongejan A
Bruysters M
Ballesteros JA
Haaksma E
Bakker RA
Pardo L
Leurs R
Source :
Nature chemical biology [Nat Chem Biol] 2005 Jul; Vol. 1 (2), pp. 98-103. Date of Electronic Publication: 2005 Jun 19.
Publication Year :
2005

Abstract

G protein-coupled receptors (GPCRs) constitute a large and functionally diverse family of transmembrane proteins. They are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways and are among the most targeted proteins in drug discovery. The detailed molecular mechanism for agonist-induced activation of rhodopsin-like GPCRs has not yet been described. Using a combination of site-directed mutagenesis and molecular modeling, we characterized important steps in the activation of the human histamine H1 receptor. Both Ser3.36 and Asn7.45 are important links between histamine binding and previously proposed conformational changes in helices 6 and 7. Ser3.36 acts as a rotamer toggle switch that, upon agonist binding, initiates the activation of the receptor through Asn7.45. The proposed transduction involves specific residues that are conserved among rhodopsin-like GPCRs.

Details

Language :
English
ISSN :
1552-4450
Volume :
1
Issue :
2
Database :
MEDLINE
Journal :
Nature chemical biology
Publication Type :
Academic Journal
Accession number :
16408006
Full Text :
https://doi.org/10.1038/nchembio714