Structure-Guided Optimization of SLC1A1/EAAT3-Selective Inhibitors Targeting Renal Cancer Metabolism

ABSTRACT: Renal cell carcinomas (RCCs) depend on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. Here 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 with an unclear mechanism of action. 3e binds a membrane-embedded allosteric pocket accessible only in the apo state, when SLC1A1 is unbound to substrate and sodium, and likely prevents sodium and substrate binding. Moreover, by forming a wedge between the trimerization domain and the substrate-binding transport domain, alongside a cholesterol moiety from the lipid bilayer, 3e blocks SLC1A1's elevator-like movements that support the transport cycl

SUBMITTER: Pooneh Koochaki 

PROVIDER: S-SCDT-10_1038-S44318-026-00776-2 | biostudies-other |

REPOSITORIES: biostudies-other