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- EMDB-40920: Human liver-type glutaminase (Apo form) -

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Basic information

Entry
Database: EMDB / ID: EMD-40920
TitleHuman liver-type glutaminase (Apo form)
Map data
Sample
  • Complex: Tetrameric form of Glutaminase liver isoform
    • Protein or peptide: Glutaminase liver isoform, mitochondrial
KeywordsMetabolic / Cancer / HYDROLASE
Function / homology
Function and homology information


L-glutamine catabolic process / glutamate biosynthetic process / Glutamate and glutamine metabolism / glutaminase / Glutamate Neurotransmitter Release Cycle / glutaminase activity / amino acid metabolic process / reactive oxygen species metabolic process / TP53 Regulates Metabolic Genes / regulation of apoptotic process ...L-glutamine catabolic process / glutamate biosynthetic process / Glutamate and glutamine metabolism / glutaminase / Glutamate Neurotransmitter Release Cycle / glutaminase activity / amino acid metabolic process / reactive oxygen species metabolic process / TP53 Regulates Metabolic Genes / regulation of apoptotic process / mitochondrial matrix / mitochondrion
Similarity search - Function
Glutaminase, EF-hand domain / EF-hand domain / Glutaminase / Glutaminase / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Beta-lactamase/transpeptidase-like / Ankyrin repeat-containing domain superfamily
Similarity search - Domain/homology
Glutaminase liver isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.12 Å
AuthorsFeng S / Aplin C / Nguyen T-TT / Milano SK / Cerione RA
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM122575 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201402 United States
National Science Foundation (NSF, United States)DMR-1719875 United States
National Institutes of Health/Office of the DirectorS10OD030470-01 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA223534 United States
CitationJournal: Nat Commun / Year: 2024
Title: Filament formation drives catalysis by glutaminase enzymes important in cancer progression.
Authors: Shi Feng / Cody Aplin / Thuy-Tien T Nguyen / Shawn K Milano / Richard A Cerione /
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 ...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.
History
DepositionMay 30, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40920.png

Downloads & links

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Map

FileDownload / File: emd_40920.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.62 Å/pix.
x 512 pix.
= 314.88 Å		0.62 Å/pix.
x 512 pix.
= 314.88 Å		0.62 Å/pix.
x 512 pix.
= 314.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.615 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0705
Minimum - Maximum-0.09258803 - 0.25767618
Average (Standard dev.)-0.00033203827 (±0.0064814696)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 314.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40920_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40920_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tetrameric form of Glutaminase liver isoform

EntireName: Tetrameric form of Glutaminase liver isoform
Components
  • Complex: Tetrameric form of Glutaminase liver isoform
    • Protein or peptide: Glutaminase liver isoform, mitochondrial

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Supramolecule #1: Tetrameric form of Glutaminase liver isoform

SupramoleculeName: Tetrameric form of Glutaminase liver isoform / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Glutaminase liver isoform, mitochondrial

MacromoleculeName: Glutaminase liver isoform, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: glutaminase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.409719 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MRSMKALQKA LSRAGSHCGR GGWGHPSRSP LLGGGVRHHL SEAAAQGRET PHSHQPQHQD HDSSESGMLS RLGDLLFYTI AEGQERIPI HKFTTALKAT GLQTSDPRLR DCMSEMHRVV QESSSGGLLD RDLFRKCVSS NIVLLTQAFR KKFVIPDFEE F TGHVDRIF ...String:
MRSMKALQKA LSRAGSHCGR GGWGHPSRSP LLGGGVRHHL SEAAAQGRET PHSHQPQHQD HDSSESGMLS RLGDLLFYTI AEGQERIPI HKFTTALKAT GLQTSDPRLR DCMSEMHRVV QESSSGGLLD RDLFRKCVSS NIVLLTQAFR KKFVIPDFEE F TGHVDRIF EDVKELTGGK VAAYIPQLAK SNPDLWGVSL CTVDGQRHSV GHTKIPFCLQ SCVKPLTYAI SISTLGTDYV HK FVGKEPS GLRYNKLSLN EEGIPHNPMV NAGAIVVSSL IKMDCNKAEK FDFVLQYLNK MAGNEYMGFS NATFQSEKET GDR NYAIGY YLKEKKCFPK GVDMMAALDL YFQLCSVEVT CESGSVMAAT LANGGICPIT GESVLSAEAV RNTLSLMHSC GMYD FSGQF AFHVGLPAKS AVSGAILLVV PNVMGMMCLS PPLDKLGNSH RGTSFCQKLV SLFNFHNYDN LRHCARKLDP RREGA EIRN KTVVNLLFAA YSGDVSALRR FALSAMDMEQ KDYDSRTALH VAAAEGHIEV VKFLIEACKV NPFAKDRWGN IPLDDA VQF NHLEVVKLLQ DYQDSYTLSE TQAEAAAEAL SKENLESMV

UniProtKB: Glutaminase liver isoform, mitochondrial

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 329000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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