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- EMDB-40918: Human glutaminase C (Y466W) with L-Gln and Pi, filamentous form -
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Open data
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Basic information
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Title | Human glutaminase C (Y466W) with L-Gln and Pi, filamentous form | ||||||||||||||||||||||||
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![]() | Cancer / Filament / Metabolism / HYDROLASE | ||||||||||||||||||||||||
Function / homology | ![]() glutamine catabolic process / regulation of respiratory gaseous exchange by nervous system process / glutamate biosynthetic process / Glutamate and glutamine metabolism / intracellular glutamate homeostasis / Glutamate Neurotransmitter Release Cycle / glutaminase / glutaminase activity / suckling behavior / TP53 Regulates Metabolic Genes ...glutamine catabolic process / regulation of respiratory gaseous exchange by nervous system process / glutamate biosynthetic 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 | ||||||||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.35 Å | ||||||||||||||||||||||||
![]() | Feng S / Aplin C / Nguyen T-TT / Milano SK / Cerione RA | ||||||||||||||||||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 117.3 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.8 KB 15.8 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.5 KB | Display | ![]() |
Images | ![]() | 76.9 KB | ||
Filedesc metadata | ![]() | 5.9 KB | ||
Others | ![]() ![]() | 115.8 MB 115.8 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 987.7 KB | Display | ![]() |
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Full document | ![]() | 987.2 KB | Display | |
Data in XML | ![]() | 19.3 KB | Display | |
Data in CIF | ![]() | 24.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8szjMC ![]() 8szlC ![]() 8t0zC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.31 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_40918_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_40918_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Human glutaminase C (Y466W) with L-Gln and Pi
Entire | Name: Human glutaminase C (Y466W) with L-Gln and Pi |
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Components |
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-Supramolecule #1: Human glutaminase C (Y466W) with L-Gln and Pi
Supramolecule | Name: Human glutaminase C (Y466W) with L-Gln and Pi / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Glutaminase kidney isoform, mitochondrial
Macromolecule | Name: Glutaminase kidney isoform, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO / EC number: glutaminase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 65.563953 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #2: PHOSPHATE ION
Macromolecule | Name: PHOSPHATE ION / type: ligand / ID: 2 / Number of copies: 12 / Formula: PO4 |
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Molecular weight | Theoretical: 94.971 Da |
Chemical component information | ![]() ChemComp-PO4: |
-Macromolecule #3: GLUTAMINE
Macromolecule | Name: GLUTAMINE / type: ligand / ID: 3 / Number of copies: 12 / Formula: GLN |
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Molecular weight | Theoretical: 146.144 Da |
Chemical component information | ![]() ChemComp-GLN: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | helical reconstruction |
Aggregation state | filament |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE-PROPANE |
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Electron microscopy
Microscope | FEI TECNAI ARCTICA |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |