title: Predicted structures and dynamics for agonists and antagonists bound to serotonin 5-HT2B and 5-HT2C receptors.
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. (1) 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.
authors.affiliation: Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Heo
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
mesh_terms: D020816:Amino Acid Motifs; D001059:Apoproteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D055550:Protein Stability; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D001059:Apoproteins; D008024:Ligands; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists