Ligand induced conformational states of the 5-HT(1A) 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-HT(1A) receptor model in the absence of ligand, in complex with a 5-HT(1A) receptor agonist (R)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-8-OH-DPAT], in complex with a selective 5-HT(1A) receptor antagonist (S)-N-tert-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.
Department of Pharmacology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, N-9037, Tromsø, Norway. sylte@fagmed.uit.no
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002065:Buspirone / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012243:Rhodopsin / Q000737:chemistry; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics
D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081293:WAY 100135; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012243:Rhodopsin; D002065:Buspirone