PMID: 18187928Jan 12, 2008Paper

Amino acids of the human alpha1d-adrenergic receptor involved in antagonist binding

Journal of Pharmacological Sciences
Yuko NagaokaTakafumi Nagatomo

Abstract

Computer simulations of the human alpha(1d)-adrenergic receptor (alpha(1d)-AR) based on the crystal structure of rhodopsin have been combined with experimental site-directed mutagenesis to investigate the role of residues in the transmembrane domains in antagonist binding. Our results indicate that the amino acids Asp176 in the third transmembrane domain (TMD), Glu237 in TMD IV, and Ser258 in TMD V of alpha(1d)-AR were directly involved in prazosin and tamsulosin binding. The Asp176Ala mutant did not exhibit any affinity for [(3)H]prazosin and neither did it show agonist-stimulated inositol phosphates (IP) formation. On the other hand, the Glu237Ala and Ser258Ala mutant alpha(1d)-AR showed increased binding affinity for [(3)H]prazosin. Competition binding experiments showed that prazosin affinity had increased to 5-fold and 3-fold in the Glu237Ala and Ser258Ala mutants, respectively, versus wild-type; and tamsulosin affinity only increased in the Ser258Ala mutant (2-fold vs wild-type). It seems that these two residues constrain the receptor by interaction with other residues and this disruption of the interaction increased the receptor's binding affinity towards antagonists. However, the Glu237Ala and Ser258Ala mutant receptors...Continue Reading

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Citations

Apr 3, 2014·European Journal of Pharmacology·Adrian P CampbellAngela M Finch
Mar 29, 2011·Pharmacological Reports : PR·Ivan KocićPiotr Rekowski
Jan 9, 2020·The American Journal of Drug and Alcohol Abuse·Daryl I ShorterDavid A Nielsen

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