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Rational design of ASCT2 inhibitors using an integrated experimental-computational approach
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Rational design of ASCT2 inhibitors using an integrated experimental-computational approach
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Journal Article
Rational design of ASCT2 inhibitors using an integrated experimental-computational approach
2021
Overview
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.
Publisher
National Academy of Sciences
Subject
Amino Acid Transport System ASC - antagonists & inhibitors
/ Amino Acid Transport System ASC - metabolism
/ Biochemistry, Molecular Biology
/ Biophysics and Computational Biology
/ Cancer
/ Cryoelectron Microscopy - methods
/ Humans
/ Minor Histocompatibility Antigens - metabolism
/ Molecular Docking Simulation
/ Pharmaceutical Preparations - administration & dosage
