PT  - JOURNAL ARTICLE
AU  - Sansuk, Kamonchanok
AU  - Deupi, Xavier
AU  - Torrecillas, Ivan R.
AU  - Jongejan, Aldo
AU  - Nijmeijer, Saskia
AU  - Bakker, Remko A.
AU  - Pardo, Leonardo
AU  - Leurs, Rob
TI  - A Structural Insight into the Reorientation of Transmembrane Domains 3 and 5 during Family A G Protein-Coupled Receptor Activation
AID  - 10.1124/mol.110.066068
DP  - 2011 Feb 01
TA  - Molecular Pharmacology
PG  - 262--269
VI  - 79
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/79/2/262.short
4100  - http://molpharm.aspetjournals.org/content/79/2/262.full
SO  - Mol Pharmacol2011 Feb 01; 79
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.