Lys199 mutation of the human angiotensin type 1 receptor differentially affects the binding of surmountable and insurmountable non-peptide antagonists

Frederik L.P. Fierens, Patrick M.L. Vanderbeyden, Zsuzsanna Gáborik, Tam Le Minh, Jean Paul De Backer, László Hunyady, Adriaan Ijzerman, Georges Vauquelin

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)283-288
Number of pages6
JournalJRAAS - Journal of the Renin-Angiotensin-Aldosterone System
Volume1
Issue number3
DOIs
Publication statusPublished - Sep 2000

Keywords

  • Angiotensin II
  • CHO cells
  • Human AT-receptor
  • Insurmountable non-peptide antagonist
  • Mutation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology

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