Mechanism and Structure-Guided Optimization of SLC1A1/EAAT3-Selective Inhibitors in Kidney Cancer.

ABSTRACT: Renal Cell Carcinomas (RCCs) depend metabolically on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. We determined a cryo-EM structure of human SLC1A1 bound to compound 3e, a recently described SLC1A1-selective bicyclic imidazo[1,2-α]pyridine-3-amine (BIA) inhibitor. 3e binds a membrane-embedded, allosteric pocket accessible only in the apo state, when SLC1A1 is unbound to substrate and sodium. Wedged between the trimerization domain and the substrate-binding transport domain, together with a cholesterol moiety from the lipid bilayer, 3e likely prevents sodium and substrate binding, and blocks SLC1A1's elevator-like movements that are essential for transport. Mutations in

SUBMITTER: Koochaki P 

PROVIDER: S-EPMC12265667 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature