A structural insight into the reorientation of transmembrane domains 3 and 5 during family A G protein-coupled receptor activation

Kamonchanok Sansuk, Xavier Deupi, Ivan R. Torrecillas, Aldo Jongejan, Saskia Nijmeijer, Remko A. Bakker, Leonardo Pardo, Rob Leurs

Research output: Contribution to journalArticleResearchpeer-review

53 Citations (Scopus)

Abstract

Rearrangement of transmembrane domains (TMs) 3 and 5 after agonist binding is necessary for stabilization of the active state of class A G protein-coupled receptors (GPCRs). Using sitedirected mutagenesis and functional assays, we provide the first evidence that the TAS(I/V) sequence motif at positions 3.37 to 3.40, highly conserved in aminergic receptors, plays a key role in the activation of the histamine H1 receptor. By combining these data with structural information from X-ray crystallography and computational modeling, we suggest that Thr3.37 interacts with TM5, stabilizing the inactive state of the receptor, whereas the hydrophobic side chain at position 3.40, highly conserved in the whole class A GPCR family, facilitates the reorientation of TM5. We propose that the structural change of TM5 during the process of GPCR activation involves a local Pro5.50-induced unwinding of the helix, acting as a hinge, and the highly conserved hydrophobic Ile3.40 side chain, acting as a pivot. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.
Original languageEnglish
Pages (from-to)262-269
JournalMolecular Pharmacology
Volume79
DOIs
Publication statusPublished - 1 Feb 2011

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