Identification of nonconserved amino acids in the AT1 receptor which comprise a general binding site for biphenylimidazole antagonists

FEBS Letters

Zheng, Wei²  Nirula, Vaneet²  Kathryn, Sandberg²  Krishnamurthi, Kamakshi¹ 

[1] Department of Physiology and Biophysics, Georgetown University Medical Center, 4000 Reservoir Road, NW, Washington, DC 20007, USA;Division of Nephrology and Hypertension, Department of Medicine, Georgetown University Medical Center, 4000 Reservoir Road, NW, Washington, DC 20007, USA

关键词: Angiotensin AT1 receptor;    Nonpeptide antagonist;    Biphenylimidazole;    Imidazoleacrylic acid;    Site-directed mutagenesis;    RAS;    renin angiotensin system;    Ang II;    angiotensin II;    AT receptor;    angiotensin receptor;    rAT1b;    rat (Sprague-Dawley) angiotensin receptor type 1b;    xATa;    frog (Xenopus laevis) angiotensin receptor type a;    xCM46;    xATa combinatorial mutant receptor defined in Table 1;    COS-7 monkey kidney epithelial cells;    TM;    transmembrane;   

DOI  :  10.1016/0014-5793(96)00961-1

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Mutational analysis based on pharmacological differences between mammalian and amphibian angiotensin II receptors (AT receptors) previously led to construction of a mutant receptor that gained >25000-fold affinity for the biphenylimidazole, Losartan. This variant frog receptor also bound with high affinity other nonpeptides in the biphenylimidazole chemical class according to the following rank order of potency (expressed in F_mut values = mutant IC₅₀/rAT_1b IC₅₀): Losartan, 0.91; L-162,389, 1.0; L-163,491, 1.9; L-158,809, 3.5; L-163,017, 3.9; SC-51,316, 3.9. In contrast, the imidazoleacrylic acids, SKF-108,566 (F_mut = 160) and SB-203,220 (F_mut = 170), bound with markedly less affinity. Thus, nonconserved residues determining the molecular requirements for biphenylimidazole recognition are conserved in general, but are not identical to nonconserved residues necessary for high affinity binding of imidazoleacrylic acids.

【 授权许可】

Unknown