Homology modeling informs ligand discovery for the glutamine transporter ASCT2

Author(s)
Rachel Ann A. Garibsingh, Nicholas J. Otte, Elias Ndaru, Claire Colas, Christof Grewer, Jeff Holst, Avner Schlessinger
Abstract

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.

Organisation(s)
External organisation(s)
Icahn School of Medicine at Mount Sinai, New York, The University of Sydney, State University of New York, Binghamton
Journal
Frontiers in Chemistry
Volume
6
ISSN
2296-2646
DOI
https://doi.org/10.3389/fchem.2018.00279
Publication date
07-2018
Peer reviewed
Yes
Austrian Fields of Science 2012
Chemical biology
Keywords
ASJC Scopus subject areas
Portal url
https://ucris.univie.ac.at/portal/en/publications/homology-modeling-informs-ligand-discovery-for-the-glutamine-transporter-asct2(2266f672-1fd3-4ea3-93de-0d6ac830dfb8).html