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

Year: 2011

DOI: 10.1021/ci100375b

PMCID: PMC3070210

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.