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Homology Modeling Informs Ligand Discovery for the Glutamine Transporter ASCT2.
Garibsingh, Rachel-Ann A; Otte, Nicholas J; Ndaru, Elias; Colas, Claire; Grewer, Christof; Holst, Jeff; Schlessinger, Avner.
Afiliación
  • Garibsingh RA; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
  • Otte NJ; Origins of Cancer Program, Centenary Institute, University of Sydney, Sydney, NSW, Australia.
  • Ndaru E; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
  • Colas C; Department of Chemistry, Binghamton University, Binghamton, NY, United States.
  • Grewer C; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
  • Holst J; Department of Chemistry, Binghamton University, Binghamton, NY, United States.
  • Schlessinger A; Origins of Cancer Program, Centenary Institute, University of Sydney, Sydney, NSW, Australia.
Front Chem ; 6: 279, 2018.
Article en En | MEDLINE | ID: mdl-30137742
The Alanine-Serine-Cysteine transporter (SLC1A5, ASCT2), is a neutral amino acid exchanger involved in the intracellular homeostasis of amino acids in peripheral tissues. Given its role in supplying glutamine to rapidly proliferating cancer cells in several tumor types such as triple-negative breast cancer and melanoma, ASCT2 has been identified as a key drug target. Here we use a range of computational methods, including homology modeling and ligand docking, in combination with cell-based assays, to develop hypotheses for structure-function relationships in ASCT2. We perform a phylogenetic analysis of the SLC1 family and its prokaryotic homologs to develop a useful multiple sequence alignment for this protein family. We then generate homology models of ASCT2 in two different conformations, based on the human EAAT1 structures. Using ligand enrichment calculations, the ASCT2 models are then compared to crystal structures of various homologs for their utility in discovering ASCT2 inhibitors. We use virtual screening, cellular uptake and electrophysiology experiments to identify a non-amino acid ASCT2 inhibitor that is predicted to interact with the ASCT2 substrate binding site. Our results provide insights into the structural basis of substrate specificity in the SLC1 family, as well as a framework for the design of future selective and potent ASCT2 inhibitors as cancer therapeutics.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Chem Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Chem Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza