TY - JOUR 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 SP - 262 LP - 269 DO - 10.1124/mol.110.066068 VL - 79 IS - 2 AU - Kamonchanok Sansuk AU - Xavier Deupi AU - Ivan R. Torrecillas AU - Aldo Jongejan AU - Saskia Nijmeijer AU - Remko A. Bakker AU - Leonardo Pardo AU - Rob Leurs Y1 - 2011/02/01 UR - http://molpharm.aspetjournals.org/content/79/2/262.abstract N2 - 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. ER -