9P4X
Human EAAT3 with compound 3e and cholesterol bound at inward facing state
This is a non-PDB format compatible entry.
Summary for 9P4X
Entry DOI | 10.2210/pdb9p4x/pdb |
EMDB information | 71288 |
Descriptor | Excitatory amino acid transporter 3, (4R)-8-bromo-2-(furan-2-yl)-N-(2-methylphenyl)imidazo[1,2-a]pyridin-3-amine, CHOLESTEROL, ... (4 entities in total) |
Functional Keywords | heaaat3, allosteric inhibitor, transport protein |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 1 |
Total formula weight | 58416.70 |
Authors | |
Primary citation | Koochaki, P.,Qiu, B.,Coker, J.A.,Earsley, A.,Wang, N.S.,Romigh, T.,Goins, C.M.,Stauffer, S.R.,Boudker, O.,Chakraborty, A.A. Mechanism and Structure-Guided Optimization of SLC1A1/EAAT3-Selective Inhibitors in Kidney Cancer. Biorxiv, 2025 Cited by PubMed 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 , a recently described SLC1A1-selective bicyclic imidazo[1,2- ]pyridine-3-amine (BIA) inhibitor. binds a membrane-embedded, allosteric pocket accessible only in the 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, likely prevents sodium and substrate binding, and blocks SLC1A1's elevator-like movements that are essential for transport. Mutations in this pocket abolish binding and counteract 's cytotoxicity in RCC cells, confirming on-target activity and explaining SLC1A1 selectivity. A structure-guided medicinal chemistry effort yielded two new, SLC1A1- selective BIA derivatives, PBJ1 and PBJ2, with enhanced cytotoxicity resulting from the inhibition of SLC1A1-dependent aspartate, glutamate, and cysteine metabolic pathways. PubMed: 40672197DOI: 10.1101/2025.07.03.663021 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (2.76 Å) |
Structure validation
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