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- PDB-8bsl: Human GLS in complex with compound 12 -

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Basic information

Entry
Database: PDB / ID: 8bsl
TitleHuman GLS in complex with compound 12
ComponentsGlutaminase kidney isoform, mitochondrial
KeywordsHYDROLASE / GLUTAMINASE / Thiadiazole / Pyridazine / Inhibitor
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
Chem-R90 / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsDebreczeni, J.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2019
Title: Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.
Authors: Finlay, M.R.V. / Anderton, M. / Bailey, A. / Boyd, S. / Brookfield, J. / Cairnduff, C. / Charles, M. / Cheasty, A. / Critchlow, S.E. / Culshaw, J. / Ekwuru, T. / Hollingsworth, I. / Jones, N. ...Authors: Finlay, M.R.V. / Anderton, M. / Bailey, A. / Boyd, S. / Brookfield, J. / Cairnduff, C. / Charles, M. / Cheasty, A. / Critchlow, S.E. / Culshaw, J. / Ekwuru, T. / Hollingsworth, I. / Jones, N. / Leroux, F. / Littleson, M. / McCarron, H. / McKelvie, J. / Mooney, L. / Nissink, J.W.M. / Perkins, D. / Powell, S. / Quesada, M.J. / Raubo, P. / Sabin, V. / Smith, J. / Smith, P.D. / Stark, A. / Ting, A. / Wang, P. / Wilson, Z. / Winter-Holt, J.J. / Wood, J.M. / Wrigley, G.L. / Yu, G. / Zhang, P.
History
DepositionNov 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release

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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)213,7166
Polymers212,9114
Non-polymers8052
Water13,890771
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9650 Å2
ΔGint-40 kcal/mol
Surface area60160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.993, 139.027, 177.716
Angle α, β, γ (deg.)90, 96.01, 90
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: 53227.867 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 (bacteria) / References: UniProt: O94925, glutaminase
#2: Chemical ChemComp-R90 / ~{N}-[5-[[(3~{R})-1-(5-azanyl-1,3,4-thiadiazol-2-yl)pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]-2-phenyl-ethanamide


Mass: 402.497 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18N8OS2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 771 / 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: 2.94 Å3/Da / Density % sol: 58.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: TRIS 0.1M pH 8.5, MgCl2 0.2M, PEG 3350 11%w/v

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.38→50 Å / Num. obs: 94211 / % possible obs: 95.6 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.103 / Rpim(I) all: 0.072 / Rrim(I) all: 0.126 / Net I/σ(I): 7
Reflection shellResolution: 2.38→2.46 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.516 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 9432 / Rpim(I) all: 0.362 / Rrim(I) all: 0.633 / % possible all: 97.4

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.38→47.64 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.9 / SU R Cruickshank DPI: 0.289 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.291 / SU Rfree Blow DPI: 0.222 / SU Rfree Cruickshank DPI: 0.223
RfactorNum. reflection% reflectionSelection details
Rfree0.2456 4678 -RANDOM
Rwork0.2087 ---
obs0.2105 94144 95.5 %-
Displacement parametersBiso mean: 46.73 Å2
Baniso -1Baniso -2Baniso -3
1--11.7539 Å20 Å2-4.8503 Å2
2--4.7254 Å20 Å2
3---7.0285 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 2.38→47.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12584 0 54 771 13409
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00812921HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9617442HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4491SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2172HARMONIC5
X-RAY DIFFRACTIONt_it12921HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1636SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact11452SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.23
X-RAY DIFFRACTIONt_other_torsion16.96
LS refinement shellResolution: 2.38→2.4 Å
RfactorNum. reflection% reflection
Rfree0.3238 113 -
Rwork0.29 --
obs0.2921 1883 95.93 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.8857-0.0222-0.50321.4150.07692.3593-0.032-0.23030.2338-0.23030.06560.20020.23380.2002-0.0335-0.02570.0409-0.0701-0.0332-0.029-0.108326.25-13.932411.5454
20.9371-0.1327-0.31381.3388-0.16381.5566-0.04540.10270.1380.10270.082-0.11090.138-0.1109-0.0366-0.1916-0.0154-0.1033-0.09880.0199-0.10267.2687-18.771972.9892
31.00030.21090.44371.570.0022.0163-0.0283-0.1779-0.2755-0.17790.10930.0327-0.27550.0327-0.081-0.0296-0.0204-0.0167-0.07390.0285-0.077813.776619.050513.1874
40.80420.0250.27911.60460.04311.61840.01140.1701-0.20080.17010.0529-0.0076-0.2008-0.0076-0.0643-0.12630.0065-0.0563-0.109-0.0232-0.087519.378514.231776.9719
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A136 - 546
2X-RAY DIFFRACTION2{ B|* }B137 - 546
3X-RAY DIFFRACTION3{ C|* }C136 - 546
4X-RAY DIFFRACTION4{ D|* }D138 - 545

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