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Yorodumi- EMDB-40950: Human liver-type glutaminase (K253A) with L-Gln, filamentous form -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-40950 | ||||||||||||||||||||||||
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Title | Human liver-type glutaminase (K253A) with L-Gln, filamentous form | ||||||||||||||||||||||||
Map data | |||||||||||||||||||||||||
Sample |
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Keywords | Metabolic / 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 | ||||||||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||||||||||||||
Authors | Feng S / Aplin C / Nguyen T-TT / Milano SK / Cerione RA | ||||||||||||||||||||||||
Funding support | United States, 7 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_40950.map.gz | 32.6 MB | EMDB map data format | |
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Header (meta data) | emd-40950-v30.xml emd-40950.xml | 15.5 KB 15.5 KB | Display Display | EMDB header |
Images | emd_40950.png | 68.3 KB | ||
Filedesc metadata | emd-40950.cif.gz | 5.9 KB | ||
Others | emd_40950_half_map_1.map.gz emd_40950_half_map_2.map.gz | 200.5 MB 200.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40950 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40950 | HTTPS FTP |
-Validation report
Summary document | emd_40950_validation.pdf.gz | 994.9 KB | Display | EMDB validaton report |
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Full document | emd_40950_full_validation.pdf.gz | 994.4 KB | Display | |
Data in XML | emd_40950_validation.xml.gz | 14 KB | Display | |
Data in CIF | emd_40950_validation.cif.gz | 15.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40950 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40950 | HTTPS FTP |
-Related structure data
Related structure data | 8t0zMC 8szjC 8szlC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_40950.map.gz / Format: CCP4 / Size: 34.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.058 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_40950_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_40950_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Human liver-type glutaminase (K253A) with L-Gln, filamentous form
Entire | Name: Human liver-type glutaminase (K253A) with L-Gln, filamentous form |
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Components |
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-Supramolecule #1: Human liver-type glutaminase (K253A) with L-Gln, filamentous form
Supramolecule | Name: Human liver-type glutaminase (K253A) with L-Gln, filamentous form type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Glutaminase liver isoform, mitochondrial
Macromolecule | Name: Glutaminase liver isoform, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO / EC number: glutaminase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 66.351617 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 |
-Macromolecule #2: GLUTAMINE
Macromolecule | Name: GLUTAMINE / type: ligand / ID: 2 / 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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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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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: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Applied 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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Startup model | Type of model: NONE |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |