Identification and Characterization of a Secondary Sodium-Binding Site and the Main Selectivity Determinants in the Human Concentrative Nucleoside Transporter 3
| Autor: | C. Estarellas, Marçal Pastor-Anglada, Cristina Arimany-Nardi, Xavier Barril, Axel Bidon-Chanal, A. Viel-Oliva, A. Claudio-Montero, Peter Schmidtke |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Molecular model concentrative transporters homology modeling nucleoside transport selectivity sodium-binding site Stereochemistry Blotting Western Pharmaceutical Science Biology Molecular Dynamics Simulation 03 medical and health sciences Residue (chemistry) 0302 clinical medicine Drug Discovery Humans Homology modeling Binding site Binding Sites Mutagenesis Membrane Transport Proteins Transporter Protein Structure Tertiary Molecular Docking Simulation 030104 developmental biology HEK293 Cells Biochemistry Molecular Medicine Cotransporter Nucleoside 030217 neurology & neurosurgery |
| Zdroj: | MOLECULAR PHARMACEUTICS r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname |
| ISSN: | 1543-8384 |
| Popis: | The family of concentrative Na + /nucleoside cotransporters in humans is constituted by three subtypes, namely, hCNT1, hCNT2, and hCNT3. Besides their different nucleoside selectivity, hCNT1 and hCNT2 have a Na + /nucleoside stoichiometry of 1:1, while for hCNT3 it is 2:1. This distinct stoichiometry of subtype 3 might hint the existence of a secondary sodium-binding site that is not present in the other two subtypes, but to date their three-dimensional structures remain unknown and the residues implicated in Na + binding are unclear. In this work, we have identified and characterized the Na + binding sites of hCNT3 by combining molecular modeling and mutagenesis studies. A model of the transporter was obtained by homology modeling, and key residues of two sodium-binding sites were identified and verified with a mutagenesis strategy. The structural model explains the altered sodium-binding properties of the hCNT3C602R polymorphic variant and supports previously generated data identifying the determinant residues of nucleoside selectivity, paving the way to understand how drugs can target this plasma membrane transporter. |
| Databáze: | OpenAIRE |
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