3D Model for TM Region of the AT-1 Receptor in Complex with Angiotensin II Independently Validated by Site-Directed Mutagenesis Data

• Published in: Biochemical and biophysical research communications 2001-09, Vol.286 (5), p.1204-1211
• Main Authors: Nikiforovich, Gregory V., Marshall, Garland R.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; angiotensin II; angiotensin II receptors (type 1); angiotensin receptors; Crystallography, X-Ray; G-protein coupled receptors; Histidine - chemistry; Ligands; Models, Molecular; molecular modeling; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Phenylalanine - chemistry; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin - chemistry; Receptors, Angiotensin - genetics; Rhodopsin - chemistry; Signal Transduction; Tyrosine - chemistry
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2001.5526

A three-dimensional model of the complex of angiotensin II (AII) with the transmembrane (TM) region of the angiotensin II receptor of type 1 (the AT-1 receptor) was obtained by molecular modeling procedures employing structural homology to the X-ray structure of rhodopsin. Since the modeling procedure 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. Indeed, the model brings in contact the residues of AII responsible for agonistic activity, Tyr4, His6, and Phe8, with many residues of AT-1 involved in signal transduction according to site-directed mutagenesis. The model also predicts the existence of several possible conformational pathways for transferring the binding signal through the TM region of AT-1 to the intracellular loops interacting with the G-protein.