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Published on: June 7, 2016
Lys(199) mutation of the human angiotensin type 1 receptor differentially affects the binding of surmountable and
F L Fierens1, P M Vanderheyden, Z Gáborik
1Department of Molecular and Biochemical Pharmacology, Free University of Brussels, Rode, B-1640, Belgium. ffierens@vub.ac.be
Abstract:
Many slow dissociating (insurmountable) non-peptide angiotensin type 1 receptor (AT1) antagonists contain,besides the acidic biphenyltetrazole substructure of losartan, a second acidic group to stabilise antagonist-receptor complexes. To investigate the involved basic amino-acids of the human AT1-receptor, wild-type and mutant receptors were transiently transfected in CHO-K1 cells and characterised by [3H]candesartan binding. Lys199-->Gln substitution decreased the affinity 45-fold for candesartan (95% insurmountable),18-fold for EXP3174 (70% insurmountable), 10-fold for irbesartan (40% insurmountable) and 5-fold for losartan (surmountable). His256 -->Ala substitution had only minor effects. This suggests that Lys199 is important for the tight binding of non-peptide antagonists.
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