9P4X

Human EAAT3 with compound 3e and cholesterol bound at inward facing state

これはPDB形式変換不可エントリーです。

9P4X の概要

• エントリーDOI: 10.2210/pdb9p4x/pdb
• EMDBエントリー: 71288
• 分子名称: 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)
• 機能のキーワード: heaaat3, allosteric inhibitor, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58416.70

構造登録者

Qiu, B.,Boudker, O. (登録日: 2025-06-17, 公開日: 2025-07-30)

主引用文献

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

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-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.

PubMed: 40672197
DOI: 10.1101/2025.07.03.663021

実験手法

ELECTRON MICROSCOPY (2.76 Å)