7bcq | pdb_00007bcq
ASCT2 in the presence of the inhibitor Lc-BPE (position "up") in the outward-open conformation.
Structural highlights
Function[AAAT_HUMAN] Sodium-dependent amino acids transporter that has a broad substrate specificity, with a preference for zwitterionic amino acids. It accepts as substrates all neutral amino acids, including glutamine, asparagine, and branched-chain and aromatic amino acids, and excludes methylated, anionic, and cationic amino acids (PubMed:8702519). Through binding of the fusogenic protein syncytin-1/ERVW-1 may mediate trophoblasts syncytialization, the spontaneous fusion of their plasma membranes, an essential process in placental development (PubMed:10708449, PubMed:23492904).[1] [2] [3] (Microbial infection) Acts as a cell surface receptor for Feline endogenous virus RD114.[4] [5] (Microbial infection) Acts as a cell surface receptor for Baboon M7 endogenous virus.[6] (Microbial infection) Acts as a cell surface receptor for type D simian retroviruses.[7] Publication Abstract from PubMedASCT2 (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. Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.,Garibsingh RA, Ndaru E, Garaeva AA, Shi Y, Zielewicz L, Zakrepine P, Bonomi M, Slotboom DJ, Paulino C, Grewer C, Schlessinger A Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). pii: 2104093118. doi:, 10.1073/pnas.2104093118. PMID:34507995[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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