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- EMDB-40950: Human liver-type glutaminase (K253A) with L-Gln, filamentous form -

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Basic information

Entry
Database: EMDB / ID: EMD-40950
TitleHuman liver-type glutaminase (K253A) with L-Gln, filamentous form
Map data
Sample
  • Complex: Human liver-type glutaminase (K253A) with L-Gln, filamentous form
    • Protein or peptide: Glutaminase liver isoform, mitochondrial
  • Ligand: GLUTAMINE
KeywordsMetabolic / Cancer / HYDROLASE
Function / homology
Function and homology information


glutamine catabolic process / glutamate biosynthetic process / Glutamate and glutamine metabolism / Glutamate Neurotransmitter Release Cycle / glutaminase / glutaminase activity / amino acid metabolic process / reactive oxygen species metabolic process / TP53 Regulates Metabolic Genes / regulation of apoptotic process ...glutamine catabolic process / glutamate biosynthetic process / Glutamate and glutamine metabolism / Glutamate Neurotransmitter Release Cycle / glutaminase / 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)
Methodhelical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsFeng S / Aplin C / Nguyen T-TT / Milano SK / Cerione RA
Funding support United States, 7 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 Institute of General Medical Sciences (NIH/NIGMS)U24 GM129539 United States
Simons FoundationSF349247 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
DepositionJun 1, 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_40950.png

Downloads & links

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Map

FileDownload / File: emd_40950.map.gz / Format: CCP4 / Size: 34.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.058 Å
Density
Contour LevelBy AUTHOR: 3.87
Minimum - Maximum-13.666805 - 21.008821000000001
Average (Standard dev.)-0.0014385498 (±0.97848326)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin1130105
Dimensions150384159
Spacing159150384
CellA: 168.222 Å / B: 158.7 Å / C: 406.27197 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40950_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_40950_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 : Human liver-type glutaminase (K253A) with L-Gln, filamentous form

EntireName: Human liver-type glutaminase (K253A) with L-Gln, filamentous form
Components
  • Complex: Human liver-type glutaminase (K253A) with L-Gln, filamentous form
    • Protein or peptide: Glutaminase liver isoform, mitochondrial
  • Ligand: GLUTAMINE

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Supramolecule #1: Human liver-type glutaminase (K253A) with L-Gln, filamentous form

SupramoleculeName: Human liver-type glutaminase (K253A) with L-Gln, filamentous form
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 12 / Enantiomer: LEVO / EC number: glutaminase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.351617 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 GLRYNALSLN 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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Macromolecule #2: GLUTAMINE

MacromoleculeName: GLUTAMINE / type: ligand / ID: 2 / Number of copies: 12 / Formula: GLN
Molecular weightTheoretical: 146.144 Da
Chemical component information

ChemComp-GLN:
GLUTAMINE / Glutamine

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Helical parameters - Δz: 66.0 Å
Applied symmetry - Helical parameters - Δ&Phi: 48 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 48000

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