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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-hydroxytryptamine1A receptor

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Journal of Biomedical Science

Abstract

A three-dimensional molecular model of the transmembrane domain of the 5-HT1A receptor (5-HT1AR) 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-HT1AR 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-HT1AR 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-HT1AR model suggest a trigger of the receptor activation mechanism resulting from ligand binding. The antagonist-binding pocket of the human 5-HT1AR 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.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Mount Sinai School of Medicine of the City University of New York, New York, N.Y., USA

    Leonardo Pardo MD & Harel Weinstein

  2. Department of Pharmacology, Mount Sinai School of Medicine of the City University of New York, New York, N.Y., USA

    Harel Weinstein

  3. Laboratori de Medicina Computacional, Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain

    Leonardo Pardo MD & Montserrat Batlle

  4. Unitat de Biofísica, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain

    Mireia Duñach

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Pardo, L., Batlle, M., Duñach, M. et al. Structure and activity of membrane receptors: Modeling and computational simulation of ligand recognition in a three-dimensional model of the 5-hydroxytryptamine1A receptor. J Biomed Sci 3, 98–107 (1996). https://doi.org/10.1007/BF02255537

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  • DOI: https://doi.org/10.1007/BF02255537

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