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

摘要

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