@article {Hoe1404, author = {Kwang-Lae Hoe and Juan M. Saavedra}, title = {Site-Directed Mutagenesis of the Gerbil and Human Angiotensin II AT1 Receptors Identifies Amino Acid Residues Attributable to the Binding Affinity for the Nonpeptidic Antagonist Losartan}, volume = {61}, number = {6}, pages = {1404--1415}, year = {2002}, doi = {10.1124/mol.61.6.1404}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Gerbil angiotensin II AT1 receptors have more than 90\% amino acid sequence homology with human AT1 receptors and similar affinity for the natural peptide agonist angiotensin II. However, their binding affinity for the biphenylimidazole AT1 receptor antagonist losartan is greatly reduced compared with the hAT1 receptor (400 times lower for the gAT1A receptor and 40 times lower for the gAT1Breceptor cloned here). Gain- and loss-of-function site-directed mutagenesis revealed that in gerbil and human AT1receptors, the amino acid most important for losartan binding is located in position 108, followed by 107, both in transmembrane (TM) III. In both gerbil and human AT1 receptors, the effect of G107S and I108V mutants is cumulative. Mutation L195M in TM V is very important, when combined with mutations G107S and I108V, for both gerbil and human AT1 receptors. In the gerbil, less important amino acids are located in positions 150/151 (TM IV) and 177 in the extracellular loop 2. The study of gerbil natural mutants allowed us to advance our understanding of amino acids selectively involved in the determination of antagonist affinity for gerbil and, most importantly, for human angiotensin II AT1 receptors.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/61/6/1404}, eprint = {https://molpharm.aspetjournals.org/content/61/6/1404.full.pdf}, journal = {Molecular Pharmacology} }