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 couple d receptor as a response on agonist stimulus and the molecular events leadi ng to blockade of the signal transduction by antagonists are not well under stood. In the present study, the AMBER 5.0 force field was used for compara tive molecular dynamics simulations of a 5-HT1A receptor model in the absen ce 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 agon ist, buspirone. In the simulations, the agonist induced larger conformation al changes into transmembrane helix 3 and 6 than into the other helices, wh ile the main conformational differences between the agonist bound receptor and the antagonist bound receptor were in transmembrane helix 5 and 6. Duri ng the simulations, all the three ligands constrained the helical movements compared to those observed in the receptor without any ligand. (C) 2001 El sevier Science B.V. All rights reserved.