Comparative molecular dynamics simulations of uncomplexed, 'agonist-bound' and 'antagonist-bound' alpha1A adrenoceptor models

Biochem Biophys Res Commun. 2005 Aug 5;333(3):737-41. doi: 10.1016/j.bbrc.2005.05.159.

Abstract

Molecular dynamics simulations (2 ns) were conducted on a homology model of the alpha1A adrenoceptor complexed with agonists and antagonists to examine the various receptor conformations induced. These simulations yield insights into the binding site interactions of the active and inactive states of the receptor. Furthermore, our analysis allowed for the selection of candidate sites for future mutagenesis experiments such as of Glu-180, which may be important for antagonist binding. The interactions of conserved residues of the DRY motif in TM-III and the NPxxY motif in TM-VII in the alpha1A adrenoceptor complexes were also examined. The major differences lie in the role of residue Arg-124, which for the agonist complexes formed additional interactions with residues of intracellular loops I and II. Alternatively, for the antagonist complexes, additional interactions were observed for Asn-322 with residues of TM-II and TM-VII.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Agonists / metabolism
  • Adrenergic alpha-Agonists / pharmacology*
  • Adrenergic alpha-Antagonists / metabolism
  • Adrenergic alpha-Antagonists / pharmacology*
  • Ligands
  • Protein Binding
  • Receptors, Adrenergic, alpha-1 / chemistry*
  • Receptors, Adrenergic, alpha-1 / metabolism

Substances

  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Ligands
  • Receptors, Adrenergic, alpha-1