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 http://resolver.caltech.edu/CaltechAUTHORS:20110329-102438454
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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.
|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.|
|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.|
|Deposited By:||Tony Diaz|
|Deposited On:||29 Mar 2011 17:35|
|Last Modified:||26 Dec 2012 13:07|
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