Open AccessRational design of ASCT2 inhibitors using an integrated experimental-computational approach
Author(s) -
Rachel Ann A. Garibsingh,
Elias Ndaru,
A.A. Garaeva,
Yueyue Shi,
Laura Zielewicz,
Paul Zakrepine,
Massimiliano Bonomi,
Dirk Jan Slotboom,
Cristina Paulino,
Christof Grewer,
Avner Schlessinger
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2104093118
Subject(s) - rational design , chemistry , amino acid , transporter , intracellular , biophysics , cancer cell , biochemistry , nanotechnology , cancer , biology , materials science , genetics , gene
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.