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8SZJ

Human glutaminase C (Y466W) with L-Gln and Pi, filamentous form

Summary for 8SZJ
Entry DOI10.2210/pdb8szj/pdb
EMDB information40918
DescriptorGlutaminase kidney isoform, mitochondrial, PHOSPHATE ION, GLUTAMINE (3 entities in total)
Functional Keywordscancer, filament, metabolism, hydrolase
Biological sourceHomo sapiens (human)
Total number of polymer chains12
Total formula weight789660.82
Authors
Feng, S.,Aplin, C.,Nguyen, T.-T.T.,Milano, S.K.,Cerione, R.A. (deposition date: 2023-05-29, release date: 2024-03-13)
Primary citationFeng, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.35 Å)
Structure validation

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PDB entries from 2024-11-20

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