On the structure and activity of membrane receptors: A computational simulation of ligand-triggered activation in a model 5-HT1A receptor

✍ Scribed by Leonardo Pardo; Harel Weinstein

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 337 KB
• Volume: 63
• Category: Article
• ISSN: 0020-7608
• DOI: 10.1002/(sici)1097-461x(1997)63:3<767::aid-qua17>3.0.co;2-1

✦ Synopsis

The relation between receptor structure and the mechanism by which ligands with different pharmacological efficacy elicit a response is analyzed in a three-dimensional w Ž .x molecular model of the human 5-HT receptor Pardo et al., J. Biomed. Sci. 3, 98 1996 .

1A

According to the model, the main interaction of the endogenous neurotransmitter Ž . Ž . serotonin 5-HT to the human 5-HT receptor consists of i the ionic interaction 1A between the protonated side-chain amine of 5-HT and the conserved Asp-116, located in Ž . Ž . transmembrane helix TMH 3; ii the hydrogen bond between the 5-OH group of 5-HT Ž . and Thr-199, located in TMH 5; and iii the complex between the aromatic indole ring of 5-HT and His-192, located in TMH 5. Ab initio quantum chemical calculations were used to position ligands in molecular models of the binding pocket of the 5-HT receptor 1A consisting of these interacting residues. The consequences of the interactions between the ligands and the proposed recognition sites of the 5-HT receptor, reflected in the 1A electronic structure of the complexes, suggest a mechanism by which the receptor activation is triggered by ligand binding. Results from the computations show a more Ž favorable interaction of the aromatic ring of 5-HT or of the 5-HT selective agonist 1A U To whom correspondence should be addressed.