Mutational analysis of the endothelin type A receptor (ETA): interactions and model of selective ETA antagonist BMS-182874 with putative ETA receptor binding cavity

Biochemistry
M L WebbS R Krystek

Abstract

Endothelin (ET) receptor antagonism is a potential therapeutic intervention in the treatment of vascular diseases. To elucidate the mechanism of antagonist-ET receptor complex formation, the interactions of four chemically distinct antagonists were investigated using a combination of genetic and biochemical approaches. By site-specific mutagenesis we previously demonstrated that Tyr129 in the second transmembrane domain was critical for high-affinity, subtype-selective binding to the A subtype of ET (ETA) receptors [Krystek et al. (1994) J. Biol. Chem. 269, 12383-12386]. Affinities of the constrained cyclic pentapeptide BQ-123, the pyrimidinylbenzenesulfonamide bosentan, the indancarboxlic acid SB 209670, and the naphthalenesulfonamide BMS-182874 were decreased 20-1000-fold in Tyr129Ala, Tyr129Ser, and Tyr129His ETA receptor mutants. Substitution of Tyr129 with Phe or Trp did not alter the high-affinity binding of BQ-123, bosentan, or SB 209670. BMS-182874 binding affinity was decreased 10-fold in Tyr129Phe and Tyr129trp ET receptors. These data indicate a role of aromatic interactions in the binding of these antagonists to ETA receptors an, in the case of BMS-182874, also suggested a hydrogen bond with the tyrosine hydroxyl. T...Continue Reading

References

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Citations

Oct 21, 2006·Journal of Computer-aided Molecular Design·Stanley R KrystekAndrew J Tebben
Sep 2, 1999·Journal of Cardiovascular Pharmacology·P A ModestiG G Neri Serneri
Jul 5, 2005·Expert Opinion on Investigational Drugs·V BreuM Clozel
Apr 13, 2011·Trends in Pharmacological Sciences·Jo G R De MeyMerlijn J P M T Meens
May 26, 2009·Journal of Peptide Science : an Official Publication of the European Peptide Society·Jens LättigGerd Krause
Feb 14, 2012·British Journal of Pharmacology·M G CompeerJ G R De Mey
Dec 7, 2000·Biophysical Journal·A J Orry, B A Wallace
Mar 1, 2011·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Travis P BarrGary R Strichartz
Jan 1, 1997·Medicinal Research Reviews·M L Webb, T D Meek

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