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- PDB-8jue: Crystal structure of glutaminase C in complex with compound 11 -

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Basic information

Entry
Database: PDB / ID: 8jue
TitleCrystal structure of glutaminase C in complex with compound 11
ComponentsGlutaminase kidney isoform, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Inhibitor / Complex / ANTITUMOR PROTEIN / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


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
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-V59 / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MAD / Resolution: 2.39 Å
AuthorsWang, X. / Hanyu, S. / Tingting, D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
CAMS Innovation Fund for Medical Sciences (CIFMS)CIFMS, No. 2021-I2M-1-028 United Kingdom
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Targeting the Subpocket Enables the Discovery of Thiadiazole-Pyridazine Derivatives as Glutaminase C Inhibitors.
Authors: Sun, H. / Du, T. / Yang, M. / Liu, X. / Xue, X. / Chen, K. / Lang, X. / Chen, X. / Wang, B. / Wang, X.
History
DepositionJun 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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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)236,0716
Polymers235,1234
Non-polymers9472
Water6,485360
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11430 Å2
ΔGint-47 kcal/mol
Surface area58780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.649, 139.510, 178.094
Angle α, β, γ (deg.)90.00, 93.49, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 58780.859 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLS, GLS1, KIAA0838 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O94925, glutaminase
#2: Chemical ChemComp-V59 / 2-(3-phenoxyphenyl)-N-[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]ethanamide


Mass: 473.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23N7O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 360 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.47 Å3/Da / Density % sol: 50.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 18% Polyethylene glycol 3350, 0.2 M magnesium chloride, 0.08 M 2-[4-(2-Hydroxyethyl)-1-piperazinyl]ethanesulfonicacid pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Jun 10, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.39→109.99 Å / Num. obs: 89723 / % possible obs: 94.39 % / Redundancy: 5.7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.05677 / Rpim(I) all: 0.02589 / Net I/σ(I): 22.85
Reflection shellResolution: 2.39→2.475 Å / Rmerge(I) obs: 0.2157 / Mean I/σ(I) obs: 8.65 / Num. unique obs: 9510 / CC1/2: 0.979 / Rpim(I) all: 0.09593 / Rrim(I) all: 0.2365

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MAD / Resolution: 2.39→109.99 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.919 / SU B: 7.699 / SU ML: 0.174 / Cross valid method: THROUGHOUT / ESU R: 0.294 / ESU R Free: 0.238 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24408 4490 5.1 %RANDOM
Rwork0.18875 ---
obs0.1915 84303 92.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.974 Å2
Baniso -1Baniso -2Baniso -3
1-3.31 Å2-0 Å2-0.73 Å2
2---2.18 Å20 Å2
3----1.03 Å2
Refinement stepCycle: 1 / Resolution: 2.39→109.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12436 0 68 360 12864
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01212784
X-RAY DIFFRACTIONr_bond_other_d0.0010.01611751
X-RAY DIFFRACTIONr_angle_refined_deg1.4821.64717241
X-RAY DIFFRACTIONr_angle_other_deg0.4871.56727421
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.15751577
X-RAY DIFFRACTIONr_dihedral_angle_2_deg8.151560
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.023102230
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0680.21892
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214369
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022571
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.5434.4986344
X-RAY DIFFRACTIONr_mcbond_other3.5414.4986344
X-RAY DIFFRACTIONr_mcangle_it5.3636.7267909
X-RAY DIFFRACTIONr_mcangle_other5.3636.7277910
X-RAY DIFFRACTIONr_scbond_it4.3055.0836440
X-RAY DIFFRACTIONr_scbond_other4.3055.0846441
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.5627.4099333
X-RAY DIFFRACTIONr_long_range_B_refined8.8853.7614095
X-RAY DIFFRACTIONr_long_range_B_other8.88353.74614046
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.391→2.453 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.315 364 -
Rwork0.268 6667 -
obs--99.84 %

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