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Identification of nonconserved amino acids in the AT 1 receptor which comprise a general binding site for biphenylimidazole antagonists
Author(s) -
Nirula Vaneet,
Zheng Wei,
Krishnamurthi Kamakshi,
Kathryn Sandberg
Publication year - 1996
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(96)00961-1
Subject(s) - losartan , receptor , mutant , chemistry , amino acid , binding site , losartan potassium , stereochemistry , biochemistry , biology , angiotensin ii , gene
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 IC 50 /rAT 1b IC 50 ): 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.