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TitleStructure-guided optimization of SLC1A1/EAAT3-selective inhibitors targeting renal cancer metabolism.
Journal, issue, pagesEMBO J, Vol. 45, Issue 11, Page 3763-3787, Year 2026
Publish dateApr 22, 2026
AuthorsPooneh Koochaki / Biao Qiu / Jesse A Coker / Alexander Earsley / Nancy S Wang / Todd Romigh / Christopher M Goins / Carleigh Salem / Dehui Mi / Emily Days / Joshua A Bauer / Shaun R Stauffer / Olga Boudker / Abhishek A Chakraborty /
PubMed AbstractRenal 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 ...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 cycle. Mutations in this binding pocket abolish the 3e interaction and counteract 3e's cytotoxicity in RCC cells, confirming on-target activity and explaining SLC1A1 selectivity. The subsequent design of two new SLC1A1-selective BIA derivatives, PBJ1 and PBJ2, was directed by the SLC1A1-3e structures; both inhibited SLC1A1-dependent aspartate, glutamate, and cysteine metabolism and showed enhanced cytotoxicity.
External linksEMBO J / PubMed:42020573 / PubMed Central
MethodsEM (single particle)
Resolution3.11 - 3.24 Å
Structure data

EMDB-75048: Human Excitatory Amino Acid Transporter 3 in 300 mM potassium and 0.1 mM Cmpd 3e in the intermediate outward-facing (iOFS) state
Method: EM (single particle) / Resolution: 3.11 Å

EMDB-75049: Human Excitatory Amino Acid Transporter 3 in 300 mM potassium and 0.1 mM Cmpd 3e in the outward-facing (OFS) state
Method: EM (single particle) / Resolution: 3.24 Å

Source
  • Homo sapiens (human)

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