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- PDB-6ume: Crystal structure of human GAC in complex with inhibitor UPGL00012 -

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Basic information

Entry
Database: PDB / ID: 6ume
TitleCrystal structure of human GAC in complex with inhibitor UPGL00012
ComponentsGlutaminase kidney isoform, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / inhibitor / complex / HYDROLASE / 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-QAJ / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsHuang, Q. / Cerione, R.A.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)GM122575 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)GM124166 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)CA201402 United States
Citation
Journal: To Be Published
Title: Crystal structure of human GAC in complex with inhibitor UPGL00012
Authors: Huang, Q. / Cerione, R.A.
#1: Journal: 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.A. / Zhang, C. / McDermott, L.A. / Iyer, P. / O'Neill, J. / Reimer, S. / Cerione, R.A. / Katt, W.P.
#2: Journal: Bioorg. Med. Chem. / Year: 2016
Title: Design and evaluation of novel glutaminase inhibitors.
Authors: McDermott, L.A. / Iyer, P. / Vernetti, L. / Reimer, S. / Sun, J. / Boby, M. / Yang, T. / Fioravanti, M. / O'Neill, J. / Wang, L. / Drakes, D. / Katt, W.P. / Huang, Q. / Cerione, R.A.
#3: Journal: J. Biol. Chem. / Year: 2016
Title: Mechanistic Basis of Glutaminase Activation: A KEY ENZYME THAT PROMOTES GLUTAMINE METABOLISM IN CANCER CELLS.
Authors: Li, Y. / Erickson, J.W. / Stalnecker, C.A. / Katt, W.P. / Huang, Q. / Cerione, R.A. / Ramachandran, S.
History
DepositionOct 9, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)233,1696
Polymers232,0964
Non-polymers1,0732
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8880 Å2
ΔGint-30 kcal/mol
Surface area64590 Å2
Unit cell
Length a, b, c (Å)100.872, 139.088, 178.237
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
31
41

NCS domain segments:

Ens-ID: 1 / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: ARG / End label comp-ID: ARG / Auth seq-ID: 137 - 544 / Label seq-ID: 66 - 473

Dom-IDComponent-IDSelection detailsAuth asym-IDLabel asym-ID
11chain 'A'AA
22(chain 'B' and resid 137 through 545)BB
33(chain 'C' and resid 137 through 545)CC
44(chain 'D' and resid 137 through 545)DD

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Components

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


Mass: 58023.996 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 (E. coli) / References: UniProt: O94925, glutaminase
#2: Chemical ChemComp-QAJ / 2-(pyridin-3-yl)-N-(5-{4-[(5-{[(pyridin-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)amino]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)acetamide


Mass: 536.632 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N10O2S2 / Feature type: SUBJECT OF INVESTIGATION
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: 2.69 Å3/Da / Density % sol: 54.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 12% PEG6000, 1.0 M LiCl pH8.0 / PH range: 8-8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: A1 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: May 29, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 121885 / % possible obs: 99.2 % / Redundancy: 3.7 % / Biso Wilson estimate: 57.88 Å2 / Rrim(I) all: 0.179 / Rsym value: 0.167 / Net I/σ(I): 8.89
Reflection shellResolution: 2.8→2.85 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 1.05 / Num. unique obs: 5554 / CC1/2: 0.811 / Rsym value: 0.47 / % possible all: 91.2

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Processing

Software
NameVersionClassification
PHENIX1.17_3644refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d3o

5d3o


Resolution: 2.9→24.46 Å / SU ML: 0.3579 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 39.7949
RfactorNum. reflection% reflection
Rfree0.2887 1761 3.16 %
Rwork0.2269 --
obs0.2288 55723 99.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 71.57 Å2
Refinement stepCycle: LAST / Resolution: 2.9→24.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12772 0 74 0 12846
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011113142
X-RAY DIFFRACTIONf_angle_d1.472617737
X-RAY DIFFRACTIONf_chiral_restr0.07481938
X-RAY DIFFRACTIONf_plane_restr0.00952287
X-RAY DIFFRACTIONf_dihedral_angle_d16.25291771
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.980.42851330.3474086X-RAY DIFFRACTION99.29
2.98-3.070.39181340.33074116X-RAY DIFFRACTION99.32
3.07-3.160.38411330.32754104X-RAY DIFFRACTION99.44
3.16-3.280.38311310.31724068X-RAY DIFFRACTION99.2
3.28-3.410.35331350.27724120X-RAY DIFFRACTION98.88
3.41-3.560.3591350.25314114X-RAY DIFFRACTION99.16
3.56-3.750.32551340.2314149X-RAY DIFFRACTION99.54
3.75-3.980.24861340.20924130X-RAY DIFFRACTION99.28
3.98-4.290.21921360.19064167X-RAY DIFFRACTION99.75
4.29-4.720.23991380.17234173X-RAY DIFFRACTION99.54
4.72-5.40.20671380.18684218X-RAY DIFFRACTION99.54
5.4-6.770.34191370.2274235X-RAY DIFFRACTION99.84
6.77-24.460.24061430.18534282X-RAY DIFFRACTION96.98
Refinement TLS params.Method: refined / Origin x: -54.4876097038 Å / Origin y: 37.277010657 Å / Origin z: -31.2962188203 Å
111213212223313233
T0.796498471123 Å2-0.0346111308794 Å20.0259745934237 Å2-0.340802269099 Å20.0561470321179 Å2--0.349056845173 Å2
L0.358234976457 °20.0295455150775 °2-0.00438888028965 °2-0.275747296112 °20.180637139964 °2--0.207154131295 °2
S-0.0427833755174 Å °0.125739478758 Å °-0.0299607186778 Å °-0.136516913985 Å °0.0444044122511 Å °0.00770590504325 Å °0.158179364367 Å °0.00388539911671 Å °0.00199983955079 Å °
Refinement TLS groupSelection details: all

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