RT Journal Article
SR Electronic
T1 A Structural Insight into the Reorientation of Transmembrane Domains 3 and 5 during Family A G Protein-Coupled Receptor Activation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 262
OP 269
DO 10.1124/mol.110.066068
VO 79
IS 2
A1 Kamonchanok Sansuk
A1 Xavier Deupi
A1 Ivan R. Torrecillas
A1 Aldo Jongejan
A1 Saskia Nijmeijer
A1 Remko A. Bakker
A1 Leonardo Pardo
A1 Rob Leurs
YR 2011
UL http://molpharm.aspetjournals.org/content/79/2/262.abstract
AB 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 site-directed 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.