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- EMDB-40918: Human glutaminase C (Y466W) with L-Gln and Pi, filamentous form -

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Basic information

Entry
Database: EMDB / ID: EMD-40918
TitleHuman glutaminase C (Y466W) with L-Gln and Pi, filamentous form
Map data
Sample
  • Complex: Human glutaminase C (Y466W) with L-Gln and Pi
    • Protein or peptide: Glutaminase kidney isoform, mitochondrial
  • Ligand: PHOSPHATE IONPhosphate
  • Ligand: GLUTAMINE
KeywordsCancer / Filament / Metabolism / HYDROLASE
Function / homology
Function and homology information


glutamine catabolic process / glutamate biosynthetic process / regulation of respiratory gaseous exchange by nervous system process / Glutamate and glutamine metabolism / intracellular glutamate homeostasis / Glutamate Neurotransmitter Release Cycle / glutaminase / glutaminase activity / suckling behavior / TP53 Regulates Metabolic Genes ...glutamine catabolic process / glutamate biosynthetic process / regulation of respiratory gaseous exchange by nervous system process / Glutamate and glutamine metabolism / intracellular glutamate homeostasis / Glutamate Neurotransmitter Release Cycle / glutaminase / glutaminase activity / suckling behavior / TP53 Regulates Metabolic Genes / chemical synaptic transmission / protein homotetramerization / mitochondrial matrix / synapse / mitochondrion / cytosol
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 kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.35 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
DepositionMay 29, 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_40918.png

Downloads & links

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Map

FileDownload / File: emd_40918.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.31 Å
Density
Contour LevelBy AUTHOR: 0.233
Minimum - Maximum-1.1375973 - 1.5996908
Average (Standard dev.)-0.00097549014 (±0.04745242)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 419.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40918_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_40918_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 glutaminase C (Y466W) with L-Gln and Pi

EntireName: Human glutaminase C (Y466W) with L-Gln and Pi
Components
  • Complex: Human glutaminase C (Y466W) with L-Gln and Pi
    • Protein or peptide: Glutaminase kidney isoform, mitochondrial
  • Ligand: PHOSPHATE IONPhosphate
  • Ligand: GLUTAMINE

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Supramolecule #1: Human glutaminase C (Y466W) with L-Gln and Pi

SupramoleculeName: Human glutaminase C (Y466W) with L-Gln and Pi / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Glutaminase kidney isoform, mitochondrial

MacromoleculeName: Glutaminase kidney 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: 65.563953 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MMRLRGSGML RDLLLRSPAG VSATLRRAQP LVTLCRRPRG GGRPAAGPAA AARLHPWWGG GGWPAEPLAR GLSSSPSEIL QELGKGSTH PQPGVSPPAA PAAPGPKDGP GETDAFGNSE GKELVASGEN KIKQGLLPSL EDLLFYTIAE GQEKIPVHKF I TALKSTGL ...String:
MMRLRGSGML RDLLLRSPAG VSATLRRAQP LVTLCRRPRG GGRPAAGPAA AARLHPWWGG GGWPAEPLAR GLSSSPSEIL QELGKGSTH PQPGVSPPAA PAAPGPKDGP GETDAFGNSE GKELVASGEN KIKQGLLPSL EDLLFYTIAE GQEKIPVHKF I TALKSTGL RTSDPRLKEC MDMLRLTLQT TSDGVMLDKD LFKKCVQSNI VLLTQAFRRK FVIPDFMSFT SHIDELYESA KK QSGGKVA DYIPQLAKFS PDLWGVSVCT VDGQRHSTGD TKVPFCLQSC VKPLKYAIAV NDLGTEYVHR YVGKEPSGLR FNK LFLNED DKPHNPMVNA GAIVVTSLIK QGVNNAEKFD YVMQFLNKMA GNEYVGFSNA TFQSERESGD RNFAIGYYLK EKKC FPEGT DMVGILDFYF QLCSIEVTCE SASVMAATLA NGGFCPITGE RVLSPEAVRN TLSLMHSCGM WDFSGQFAFH VGLPA KSGV AGGILLVVPN VMGMMCWSPP LDKMGNSVKG IHFCHDLVSL CNFHNYDNLR HFAKKLDPRR EGGDQRHSFG PLDYES LQQ ELALKETVWK KVSPESNEDI STTVVYRMES LGEKS

UniProtKB: Glutaminase kidney isoform, mitochondrial

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Macromolecule #2: PHOSPHATE ION

MacromoleculeName: PHOSPHATE ION / type: ligand / ID: 2 / Number of copies: 12 / Formula: PO4
Molecular weightTheoretical: 94.971 Da
Chemical component information

ChemComp-PO4:
PHOSPHATE ION / Phosphate

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Macromolecule #3: GLUTAMINE

MacromoleculeName: GLUTAMINE / type: ligand / ID: 3 / 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 TECNAI ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 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: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 68.0 Å
Applied symmetry - Helical parameters - Δ&Phi: 51 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 45000
FSC plot (resolution estimation)

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