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J Biol Chem. 1995 May 26;270(21):12846-50.

The docking of Arg2 of angiotensin II with Asp281 of AT1 receptor is essential for full agonism.

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Department of Molecular Cardiology, Cleveland Clinic Foundation, Ohio 44195-5069, USA.


The structural model of AT1 angiotensin receptor contains seven-transmembrane alpha-helices with three interhelical loops on either side of the membrane. The angiotensin II binding pocket within the receptor is not clearly defined. We showed earlier that Lys199 in transmembrane-helix-5 of the AT1 receptor binds the COOH-terminal alpha-carboxyl group of angiotensin II (Noda, K., Saad, Y., Kinoshita, A., Boyle, T. P., Graham, R. M., Husain, A., and Karnik, S. S. (1995) J. Biol. Chem. 270, 2284-2289). We now show that His183 and Asp281, both located in the extracellular domain of the AT1 receptor, are involved in binding the NH2-terminal Asp1 and Arg2 residues of angiotensin II, respectively. The Asp1/His183 interaction appears to be weak and is unlikely to be important for agonism. But the loss of Arg2/Asp281 interaction leads to partial agonism of the receptor. The action of non-peptide agonists is not affected by Asp281 mutations. These results suggest that several independent interactions between angiotensin II and AT1 receptor are necessary for full agonism. Since L-162,313 the non-peptide agonist of the AT1 receptor is a partial agonist that does not make contact with Asp281, we speculate that the degree of agonism may be increased if it is redesigned to make contacts with Asp281.

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