Ligand induced conformational states of the 5-HT1A receptor

It has been shown that G-protein coupled receptors have seven transmembrane alpha -helices, but the structural changes occurring in a G-protein coupled receptor as a response on agonist stimulus and the molecular events leading to blockade of the signal transduction by antagonists are not well understood. In the present study, the AMBER 5.0 force field was used for comparative molecular dynamics simulations of a 5-HT1A receptor model in the absence of ligand, in complex with a 5-HT1A receptor agonist (R)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-8-OH-DPAT], in complex with a selective 5-HT1A receptor antagonist (S)-N-rert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl ]-2-phenylpropanamide [(S)-WAY100135], and in complex with the partial agonist, buspirone. In the simulations, the agonist induced larger conformational changes into transmembrane helix 3 and 6 than into the other helices, while the main conformational differences between the agonist bound receptor and the antagonist bound receptor were in transmembrane helix 5 and 6. During the simulations, all the three ligands constrained the helical movements compared to those observed in the receptor without any ligand. (C) 2001 Elsevier Science B.V. All rights reserved.