Modelling the interaction of catecholamines with the a 1A Adrenoceptor towards a ligand-induced receptor structure Gemma K. Kinsella a , Isabel Rozas a,b, * & Graeme W. Watson a, * a Department of Chemistry, Trinity College, University of Dublin, Dublin 2, Ireland; b Centre for Synthesis and Chemical Biology, Trinity College, University of Dublin, Dublin 2, Ireland Received 25 February 2005; accepted 18 May 2005 Ó Springer 2005 Key words: a 1A -adrenoceptor, agonists, molecular docking, molecular dynamics, receptor activation 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 a 1A adrenoceptor. Analysis of agonist/a 1A 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. Introduction The a 1 adrenoceptors (a 1 -AR), which belong to Class A of the super family of G protein coupled receptors (GPCRs), are of particular therapeutic interest due to their important roles in the control of blood pressure and in the contraction and growth of smooth muscle. More specifically the a 1A adrenoceptor (a 1A -AR) located in large abun- dance in the prostate is thought to be influential in the condition Benign Prostatic Hyperplasia (BPH), a considerable health problem for aging men [1]. Class A GPCRs consist of a heptahelical bundle (TM I-VII), which transverses the cell membrane. They share key structural features including a disulfide bond between TM-III and the extracellular (EC) region, a tripeptide Glu/ Asp-Arg-Tyr (E/DRY) motif located at the intra- cellular end of TM-III and a common Asn-Pro-X- X-Tyr (NPxxY) motif in TM-VII [2]. To advance our understanding of the molecular structure of the a 1A -AR we recently built a homology model based on the 1l9h [3] 2.6 A ˚ resolution crystal structure of bovine rhodopsin in the inactive state [4]. Mutagenesis studies suggest specific binding interactions of the endogenous catecholamines, adrenaline (AD) and noradrenaline (ND), see Figure 1, with the a 1A -AR [5–7]. These include an interaction between the amino group of the cate- cholamines and Asp-106 in TM-III; and of the catechol hydroxyl groups with Ser-188 and Ser-192 of TM-V [8, 9]. Once GPCRs receive an agonist stimulus at their extracellular side they transfer the signal across the cell membrane and initiate a *To whom correspondence should be addressed. Fax: +353-1- 671-2826, E-mail: rozasi@tcd.ie/watsong@tcd.ie Journal of Computer-Aided Molecular Design (2005) 19: 357–367 DOI 10.1007/s10822-005-7553-1 357