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Structure and Activity of Membrane Receptors: Modeling and Computational Simulation of Ligand Recognition in a Three-Dimensional Model of the 5-Hydroxytryptamine(1A) Receptor.

Abstract：

:A three-dimensional molecular model of the transmembrane domain of the 5-HT(1A) receptor (5-HT(1A)R) is presented in the context of a general strategy for modeling the macromolecular structure of a guanine nucleotide binding, regulatory protein coupled receptor (GPCR). The model of the 5-HT(1A)R rests on the definition of the putative residues of the ligand-binding site guided by criteria based on specific models proposed from structure-activity studies and on published results of modifications of GPCRs using methods of molecular biology. The resulting requirements for matching recognition sites in the agonist-binding pocket define the molecular details of the interaction between the agonist 5-HT and the human 5-HT(1A)R that includes: (1) the interaction between the protonated amine moiety and the conserved negative Asp-116, located in TMH 3; (2) the hydrogen bond between the hydroxyl group and Thr-199, located in TMH 5; and (3) the interaction complex between the aromatic ring portion of the ligand and the neutral form of His-192, located in TMH 5. Results from quantum mechanical calculations of the interaction between an agonist and the proposed recognition pocket of the 5-HT(1A)R model suggest a trigger of the receptor activation mechanism resulting from ligand binding. The antagonist-binding pocket of the human 5-HT(1A)R is inferred from the interaction sites of pindolol with the receptor model: (1) the ionic interaction between the protonated amine of the ligand and the side chain of the conserved Asp-116, located in TMH 3; and (2) the hydrogen bonds between the ether oxygen and the hydroxyl group of the ligand and Asn-385, located in TMH 7. Use of the model is proposed to facilitate the identification of the structural elements of agonists and antagonists that are key for their specific functions, in order to achieve the design of new compounds with predetermined pharmacological properties. Copyright 1996 S. Karger AG, Basel

journal_name

J Biomed Sci

journal_title

Journal of biomedical science

authors

Pardo L,Batlle M,Duñach M,Weinstein H

doi

10.1007/BF02255537

keywords:

subject

Has Abstract

pub_date

1996-04-01 00:00:00

pages

98-107

issue

eissn

1021-7770

issn

1423-0127

pii

jbs03098

journal_volume

pub_type

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Structure and Activity of Membrane Receptors: Modeling and Computational Simulation of Ligand Recognition in a Three-Dimensional Model of the 5-Hydroxytryptamine(1A) Receptor.