Rational design of ASCT2 inhibitors using an integrated experimental-computational approach

Rachel Ann A. Garibsingh, Elias Ndaru, Alisa A. Garaeva, Yueyue Shi, Laura Zielewicz, Paul Zakrepine, Massimiliano Bonomi, Dirk J. Slotboom, Cristina Paulino, Christof Grewer, Avner Schlessinger

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26 Scopus citations


ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy. Here,we rationally designed stereospecific inhibitors exploiting specific subpockets in the substrate binding site using computational modeling and cryo-electron microscopy (cryo-EM). The final structures combined with molecular dynamics simulations reveal multiple pharmacologically relevant conformations in the ASCT2 binding site as well as a previously unknown mechanism of stereospecific inhibition. Furthermore, this integrated analysis guided the design of a series of unique ASCT2 inhibitors. Our results provide a framework for future development of cancer therapeutics targeting nutrient transport via ASCT2, as well as demonstrate the utility of combining computational modeling and cryo-EM for solute carrier ligand discovery.

Original languageEnglish
Article numbere2104093118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - 14 Sep 2021


  • Cryo-EM
  • Homology modeling
  • MD simulations
  • Membrane protein
  • Solute carrier transporter


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