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
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