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Structure paper

TitleMechanism and Structure-Guided Optimization of SLC1A1/EAAT3-Selective Inhibitors in Kidney Cancer.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateJul 7, 2025
AuthorsPooneh Koochaki / Biao Qiu / Jesse A Coker / Alexander Earsley / Nancy S Wang / Todd Romigh / Christopher M Goins / Shaun R Stauffer / Olga Boudker / Abhishek A Chakraborty /
PubMed AbstractRenal Cell Carcinomas (RCCs) depend metabolically on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. We ...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-α]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.
External linksbioRxiv / PubMed:40672197 / PubMed Central
MethodsEM (single particle)
Resolution2.56 - 2.83 Å
Structure data

71288

9p4x

EMDB-71288, PDB-9p4x:
Human EAAT3 with compound 3e and cholesterol bound at inward facing state
Method: EM (single particle) / Resolution: 2.76 Å

71289

9p4y

EMDB-71289, PDB-9p4y:
Human EAAT3 with compound 3e and digitonin.glyco-diosgenin bound at inward facing state
Method: EM (single particle) / Resolution: 2.56 Å

71290

9p4z

EMDB-71290, PDB-9p4z:
Human EAAT3 with sodium bound at inward facing state
Method: EM (single particle) / Resolution: 2.83 Å

Chemicals

PDB-1cg9:
COMPLEX RECOGNITION OF THE SUPERTYPIC BW6-DETERMINANT ON HLA-B AND-C MOLECULES BY THE MONOCLONAL ANTIBODY SFR8-B6

ChemComp-CLR:
CHOLESTEROL

ChemComp-HOH:
WATER

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

ChemComp-NA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / hEAAAT3 / allosteric inhibitor / Sodium bound

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