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The structure of human serotonin 2c G-protein-coupled receptor bound to agonists and antagonists

Bray, Jenelle K. and Goddard, William A., III (2008) The structure of human serotonin 2c G-protein-coupled receptor bound to agonists and antagonists. Journal of Molecular Graphics and Modelling, 27 (1). pp. 66-81. ISSN 1093-3263. doi:10.1016/j.jmgm.2008.02.006.

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We used the MembStruk computational procedure to predict the three-dimensional (3D) structure for the serotonin 5-HT_(2C) G-protein-coupled receptor (GPCR). Using this structure, we used the MSCDock computational procedure to predict the 3D structures for bound ligand–protein complexes for agonists such as serotonin and antagonists such as ritanserin, metergoline, and methiothepin. In addition, we predicted the SAR data for a series of psilocybin analogs, both agonists and antagonists. We performed molecular dynamics (MD) on serotonin bound to 5-HT_(2C) and we find the protein and binding site to be stable after 5 ns. We find good agreement with the currently known experimental data and we predict a number of new mutations which could be used to validate further our predicted structures. This agreement between theory and experiment suggests that our 3D structure is sufficiently accurate for use in drug design. We also compare a preliminary prediction for 5-HT_(2B) with our prediction for 5-HT_(2C) and find a difference in TM5 that contributes to different serotonin binding modes in 5-HT_(2B) and 5-HT_(2C).

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Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2008 Elsevier Inc. Received 25 October 2007; revised 25 January 2008; accepted 23 February 2008. Available online 27 March 2008. We thank the Department of Energy for the award of a Computational Science Graduate Fellowship. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jmgm.2008.02.006.
Funding AgencyGrant Number
Computational Science Graduate FellowshipUNSPECIFIED
Subject Keywords:protein structure prediction; binding site prediction; membrane proteins; G-protein-coupled receptors; serotonin receptors
Issue or Number:1
Record Number:CaltechAUTHORS:BRAjmgm08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13546
Deposited By: Tony Diaz
Deposited On:08 May 2009 17:18
Last Modified:08 Nov 2021 22:38

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