8T0Z

Human liver-type glutaminase (K253A) with L-Gln, filamentous form

8T0Z の概要

• エントリーDOI: 10.2210/pdb8t0z/pdb
• EMDBエントリー: 40950
• 分子名称: Glutaminase liver isoform, mitochondrial, GLUTAMINE (2 entities in total)
• 機能のキーワード: metabolic, cancer, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 797973.13

構造登録者

Feng, S.,Aplin, C.,Nguyen, T.-T.T.,Milano, S.K.,Cerione, R.A. (登録日: 2023-06-01, 公開日: 2024-03-13)

主引用文献

Feng, S.,Aplin, C.,Nguyen, T.T.,Milano, S.K.,Cerione, R.A.
Filament formation drives catalysis by glutaminase enzymes important in cancer progression.
Nat Commun, 15:1971-1971, 2024

PubMed Abstract: The glutaminase enzymes GAC and GLS2 catalyze the hydrolysis of glutamine to glutamate, satisfying the 'glutamine addiction' of cancer cells. They are the targets of anti-cancer drugs; however, their mechanisms of activation and catalytic activity have been unclear. Here we demonstrate that the ability of GAC and GLS2 to form filaments is directly coupled to their catalytic activity and present their cryo-EM structures which provide a view of the conformational states essential for catalysis. Filament formation guides an 'activation loop' to assume a specific conformation that works together with a 'lid' to close over the active site and position glutamine for nucleophilic attack by an essential serine. Our findings highlight how ankyrin repeats on GLS2 regulate enzymatic activity, while allosteric activators stabilize, and clinically relevant inhibitors block, filament formation that enables glutaminases to catalyze glutaminolysis and support cancer progression.

PubMed: 38438397
DOI: 10.1038/s41467-024-46351-3

実験手法

ELECTRON MICROSCOPY (3.3 Å)