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Predicted Structures and Dynamics for Agonists and Antagonists Bound to Serotonin 5-HT2B and 5-HT2C Receptors

Kim, Soo-Kyung and Li, Youyong and Abrol, Ravinder and Heo, Jiyoung and Goddard, William A., III (2011) Predicted Structures and Dynamics for Agonists and Antagonists Bound to Serotonin 5-HT2B and 5-HT2C Receptors. Journal of Chemical Information and Modeling, 51 (2). pp. 420-433. ISSN 1549-9596. PMCID PMC3070210. https://resolver.caltech.edu/CaltechAUTHORS:20110329-102438454

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Abstract

Subtype 2 serotonin (5-hydroxytryptamine, 5-HT) receptors are major drug targets for schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinogens, and gastrointestinal dysfunctions.' We report here the predicted structure of 5-HT2B and 5-HT2C receptors bound to highly potent and selective 5-HT2B antagonist PRX-08066 3, (pKi: 30 nM), including the key binding residues [V103 (2.53), L132 (3.29), V190 (4.60), and L347 (6.58)] determining the selectivity of binding to 5-HT2B over 5-HT2A. We also report structures of the endogenous agonist (5 HT) and a HT2B selective antagonist 2 (1-methyl-1-1,6,7,8-tetrahydro-pyrrolo [2,3-g]quinoline-5-carboxylic acid pyridine-3-ylamide). We examine the dynamics for the agonist-and antagonist-bound HT2B receptors in explicit membrane and water finding dramatically different patterns of water migration into the NPxxY motif and the binding site that correlates with the stability of ionic locks in the D(E)RY region.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ci100375b DOIArticle
http://pubs.acs.org/doi/abs/10.1021/ci100375bPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070210PubMed CentralArticle
ORCID:
AuthorORCID
Kim, Soo-Kyung0000-0002-4498-5441
Li, Youyong0000-0002-5248-2756
Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2011 American Chemical Society. Received: September 23, 2010. Article ASAP February 07, 2011. Published In Issue February 28, 2011. This work was funded partially by Boehringer-Ingelheim and by National Institutes of Health (R01NS071112 and 1R01NS073115). We thank Dr. Henry Levenson for helpful discussion.
Funders:
Funding AgencyGrant Number
Boehringer-IngelheimUNSPECIFIED
NIHR01NS071112
NIH1R01NS073115
Issue or Number:2
PubMed Central ID:PMC3070210
Record Number:CaltechAUTHORS:20110329-102438454
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110329-102438454
Official Citation:Predicted Structures and Dynamics for Agonists and Antagonists Bound to Serotonin 5-HT2B and 5-HT2C Receptors Soo-Kyung Kim, Youyong Li, Ravinder Abrol, Jiyoung Heo, William A. Goddard III Journal of Chemical Information and Modeling 2011 51 (2), 420-433
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23154
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:29 Mar 2011 17:35
Last Modified:09 Mar 2020 13:19

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