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- PDB-5wj6: Crystal structure of glutaminase C in complex with inhibitor 2-ph... -

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Basic information

Entry
Database: PDB / ID: 5wj6
TitleCrystal structure of glutaminase C in complex with inhibitor 2-phenyl-N-{5-[4-({5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}amino)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}acetamide (UPGL-00004)
Components(Glutaminase kidney isoform, mitochondrial) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / glutaminase C / inhibitor / complex / glutamine / HYDROLASE-HYDROLASE INHIBITOR complex
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 / Ankyrin repeat-containing domain superfamily / Beta-lactamase/transpeptidase-like
Similarity search - Domain/homology
Chem-B4A / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.445 Å
AuthorsHuang, Q. / Cerione, R.A.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM040654 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM047458 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM061762 United States
CitationJournal: J. Biol. Chem. / Year: 2018
Title: Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism.
Authors: Huang, Q. / Stalnecker, C. / Zhang, C. / McDermott, L.A. / Iyer, P. / O'Neill, J. / Reimer, S. / Cerione, R.A. / Katt, W.P.
History
DepositionJul 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 10, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2018Group: Database references / Category: citation
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2018Group: Database references / Category: pdbx_related_exp_data_set
Revision 1.3Mar 21, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glutaminase kidney isoform, mitochondrial
B: Glutaminase kidney isoform, mitochondrial
C: Glutaminase kidney isoform, mitochondrial
D: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)238,7736
Polymers237,7044
Non-polymers1,0692
Water11,710650
1
A: Glutaminase kidney isoform, mitochondrial
C: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,9284
Polymers118,8592
Non-polymers1,0692
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3870 Å2
ΔGint-14 kcal/mol
Surface area31650 Å2
MethodPISA
2
B: Glutaminase kidney isoform, mitochondrial
D: Glutaminase kidney isoform, mitochondrial


Theoretical massNumber of molelcules
Total (without water)118,8452
Polymers118,8452
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3880 Å2
ΔGint-12 kcal/mol
Surface area33250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.652, 138.010, 175.769
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Glutaminase kidney isoform, mitochondrial / GLS / K-glutaminase / L-glutamine amidohydrolase


Mass: 59429.535 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLS, GLS1, KIAA0838 / Production host: Escherichia coli (E. coli) / References: UniProt: O94925, glutaminase
#2: Protein Glutaminase kidney isoform, mitochondrial / GLS / K-glutaminase / L-glutamine amidohydrolase


Mass: 59415.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLS, GLS1, KIAA0838 / Production host: Escherichia coli (E. coli) / References: UniProt: O94925, glutaminase
#3: Chemical ChemComp-B4A / 2-phenyl-N-{5-[4-({5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}amino)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}acetamide


Mass: 534.656 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H26N8O2S2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 650 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.49 Å3/Da / Density % sol: 50.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 10-15% PEG6000, 1.0 M lithium chloride, 0.1 M Tris-HCl, pH 8.5
PH range: 8.0-8.5 / Temp details: ROOM TEMPERATURE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: A1 / Wavelength: 0.978 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 31, 2014
RadiationMonochromator: diamond / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 2.445→50 Å / Num. obs: 87990 / % possible obs: 99.9 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.137 / Rsym value: 0.137 / Net I/σ(I): 17.25
Reflection shellResolution: 2.445→2.49 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.766 / Mean I/σ(I) obs: 2.08 / Rsym value: 0.766 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5FI6

5fi6


Resolution: 2.445→47.045 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.76
RfactorNum. reflection% reflectionSelection details
Rfree0.2231 1999 2.28 %random selection
Rwork0.1802 ---
obs0.1812 87827 99.35 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.445→47.045 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12779 0 74 650 13503
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913185
X-RAY DIFFRACTIONf_angle_d1.04917794
X-RAY DIFFRACTIONf_dihedral_angle_d15.2257926
X-RAY DIFFRACTIONf_chiral_restr0.0581941
X-RAY DIFFRACTIONf_plane_restr0.0062298
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4452-2.50630.26481330.23265717X-RAY DIFFRACTION94
2.5063-2.57410.30951430.2216100X-RAY DIFFRACTION100
2.5741-2.64980.24361410.21696089X-RAY DIFFRACTION100
2.6498-2.73530.27641420.21886090X-RAY DIFFRACTION100
2.7353-2.83310.26511420.20636110X-RAY DIFFRACTION100
2.8331-2.94650.25611430.20466118X-RAY DIFFRACTION100
2.9465-3.08060.21521420.19836115X-RAY DIFFRACTION100
3.0806-3.24290.25881420.19276130X-RAY DIFFRACTION100
3.2429-3.44610.21911440.1876150X-RAY DIFFRACTION100
3.4461-3.7120.21991430.17136153X-RAY DIFFRACTION100
3.712-4.08540.21191440.15326180X-RAY DIFFRACTION100
4.0854-4.67610.1921440.13936220X-RAY DIFFRACTION100
4.6761-5.88960.18231450.17126231X-RAY DIFFRACTION100
5.8896-47.05330.20751510.17976425X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 102.145 Å / Origin y: 175.3134 Å / Origin z: 30.8422 Å
111213212223313233
T0.2289 Å20.0005 Å20.0107 Å2-0.2243 Å2-0.0051 Å2--0.2056 Å2
L0.0351 °2-0.0215 °2-0.0066 °2-0.1353 °20.0036 °2--0.0755 °2
S0.0093 Å °-0.0321 Å °0.0074 Å °0.0429 Å °-0.0008 Å °0.0013 Å °-0.0033 Å °-0.0012 Å °0 Å °
Refinement TLS groupSelection details: all

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