Scientists Reveal the Reorientation of Transmembrane domains 3 and 5 during Family A GPCR Activation

The paper, entitled 'A structural insight into the reorientation of transmembrane domains 3 and 5 during family A GPCR activation', is freely available online through Aspect Journals 'Molecular Pharmacology' title

Abstract

Rearrangement of transmembrane domains (TMs) 3 and 5 following 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 3.37-3.40, 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 T3.37
interacts with TM5 stabilizing the inactive state of the receptor, while 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 P5.50-induced unwinding of the helix, acting as a hinge, and the highly
conserved hydrophobic I3.40 side chain, acting as a pivot.