Journal of Computer-Aided Molecular Design

, Volume 19, Issue 6, pp 357–367 | Cite as

Modelling the Interaction of Catecholamines with the α1A Adrenoceptor Towards a Ligand-induced Receptor Structure

  • Gemma K. Kinsella
  • Isabel Rozas
  • Graeme W. Watson
Article

Abstract

Adrenoceptors are members of the important G protein coupled receptor family for which the detailed mechanism of activation remains unclear. In this study, we have combined docking and molecular dynamics simulations to model the ligand induced effect on an homology derived human α1A adrenoceptor. Analysis of agonist/α1A adrenoceptor complex interactions focused on the role of the charged amine group, the aromatic ring, the N-methyl group of adrenaline, the beta hydroxyl group and the catechol meta and para hydroxyl groups of the catecholamines. The most critical interactions for the binding of the agonists are consistent with many earlier reports and our study suggests new residues possibly involved in the agonist-binding site, namely Thr-174 and Cys-176. We further observe a number of structural changes that occur upon agonist binding including a movement of TM-V away from TM-III and a change in the interactions of Asp-123 of the conserved DRY motif. This may cause Arg-124 to move out of the TM helical bundle and change the orientation of residues in IC-II and IC-III, allowing for increased affinity of coupling to the G-protein.

Keywords

α1A-adrenoceptor agonists molecular docking molecular dynamics receptor activation 

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Copyright information

© Springer 2005

Authors and Affiliations

  • Gemma K. Kinsella
    • 1
  • Isabel Rozas
    • 1
    • 2
  • Graeme W. Watson
    • 1
  1. 1.Department of Chemistry, Trinity CollegeUniversity of DublinDublin 2Ireland
  2. 2.Centre for Synthesis and Chemical Biology, Trinity CollegeUniversity of DublinDublin 2Ireland

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