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© Research
Publication : Proc. Natl. Acad. Sci. USA

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Proc. Natl. Acad. Sci. USA - 10 Sep 2021

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

Proc. Natl. Acad. Sci. USA 118 (2021) e21040931188

ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid trans- porter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glu- tamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy. Here, we rationally designed stereospecific inhibitors exploiting spe- cific subpockets in the substrate binding site using computational modeling and cryo-electron microscopy (cryo-EM). The final struc- tures combined with molecular dynamics simulations reveal multi- ple 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 frame- work for future development of cancer therapeutics targeting nu- trient transport via ASCT2, as well as demonstrate the utility of combining computational modeling and cryo-EM for solute carrier ligand discovery.

https://www.pnas.org/content/pnas/118/37/e2104093118.full.pdf