3D model for TM region of the AT-1 receptor in complex with angiotensin IIindependently validated by site-directed mutagenesis data

A three-dimensional model of the complex of angiotensin II (AII) with the t ransmembrane (TM) region of the angiotensin II receptor of type I (the AT-1 receptor) was obtained by molecular modeling procedures employing structur al homology to the X-ray structure of rhodopsin. Since the modeling procedu re considered only steric and energy considerations without prior knowledge of the experimental results of site-directed mutagenesis; the results with receptor mutants could be used for independent validation of the model. In deed, the model brings in contact the residues of AII responsible for agoni stic activity, Tyr(4), His(6), and Phe(8), with many residues of AT-1 invol ved in. signal transduction according to site-directed mutagenesis. The mod el also predicts the existence of several possible conformational pathways for transferring the binding signal through the TM region of AT-1 to the in tracellular loops interacting with the G-protein. (C) 2001 Academic Press.