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- PDB-6ujm: Crystal structure of human GAC in complex with inhibitor UPGL00013 -

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Basic information

Entry
Database: PDB / ID: 6ujm
TitleCrystal structure of human GAC in complex with inhibitor UPGL00013
ComponentsGlutaminase kidney isoform, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Inhibitor / Complex / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


L-glutamine catabolic process / regulation of respiratory gaseous exchange by nervous system process / glutamate biosynthetic process / Glutamate and glutamine metabolism / glutaminase / intracellular glutamate homeostasis / Glutamate Neurotransmitter Release Cycle / glutaminase activity / suckling behavior / TP53 Regulates Metabolic Genes ...L-glutamine catabolic process / regulation of respiratory gaseous exchange by nervous system process / glutamate biosynthetic process / Glutamate and glutamine metabolism / glutaminase / intracellular glutamate homeostasis / Glutamate Neurotransmitter Release Cycle / glutaminase activity / suckling behavior / TP53 Regulates Metabolic Genes / protein homotetramerization / chemical synaptic transmission / 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 / Beta-lactamase/transpeptidase-like / Ankyrin repeat / Ankyrin repeat-containing domain superfamily
Similarity search - Domain/homology
Chem-Q94 / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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 UPGL00013
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. / 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. / Rimer, S. / Sun, J. / Boby, M. / Yang, T. / Fioravanti, M. / O'Neill, J. / Wang, L. / Drakes, D. / Katt, W. / Huang, Q. / Cerione, R.
#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 3, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 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)232,8336
Polymers232,0964
Non-polymers7372
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10780 Å2
ΔGint-47 kcal/mol
Surface area61150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.298, 139.011, 177.389
Angle α, β, γ (deg.)90.000, 93.410, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
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-Q94 / N-{5-[(3R)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]amino}pyrrolidin-1-yl]-1,3,4-thiadiazol-2-yl}acetamide


Mass: 368.438 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H16N8O2S2 / 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: 3.32 Å3/Da / Density % sol: 62.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 12% PEG6000, 1.0M LiCl, pH 8.0 / 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 28, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 78825 / % possible obs: 95.4 % / Redundancy: 6.2 % / Biso Wilson estimate: 36.58 Å2 / CC1/2: 0.883 / Rrim(I) all: 0.129 / Rsym value: 0.098 / Net I/σ(I): 8.78
Reflection shellResolution: 2.5→2.54 Å / Redundancy: 5.8 % / Mean I/σ(I) obs: 1.23 / Num. unique obs: 3492 / Rrim(I) all: 0.558 / Rsym value: 0.437 / % possible all: 85.11

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d3o

5d3o


Resolution: 2.5→44.27 Å / SU ML: 0.3234 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.0591
RfactorNum. reflection% reflection
Rfree0.26 1995 2.53 %
Rwork0.2046 --
obs0.206 78763 95.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 46.1 Å2
Refinement stepCycle: LAST / Resolution: 2.5→44.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12772 0 48 0 12820
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008413112
X-RAY DIFFRACTIONf_angle_d1.107717699
X-RAY DIFFRACTIONf_chiral_restr0.05491938
X-RAY DIFFRACTIONf_plane_restr0.00722283
X-RAY DIFFRACTIONf_dihedral_angle_d8.86727851
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.560.30241200.25934830X-RAY DIFFRACTION84.38
2.56-2.630.30821390.2435127X-RAY DIFFRACTION89.06
2.63-2.710.31931430.24635267X-RAY DIFFRACTION92.05
2.71-2.790.3151280.22315361X-RAY DIFFRACTION93.86
2.79-2.890.28211420.22975473X-RAY DIFFRACTION94.02
2.89-3.010.27921420.24455378X-RAY DIFFRACTION94.8
3.01-3.150.30951400.23985491X-RAY DIFFRACTION95.72
3.15-3.310.29161410.22465548X-RAY DIFFRACTION96.18
3.31-3.520.26461430.21135629X-RAY DIFFRACTION97.19
3.52-3.790.29371540.20065662X-RAY DIFFRACTION98.61
3.79-4.170.23461470.18315691X-RAY DIFFRACTION99.27
4.17-4.780.21251500.16155715X-RAY DIFFRACTION99.47
4.78-6.010.23191470.18595791X-RAY DIFFRACTION99.71
6.01-44.270.22171590.19415805X-RAY DIFFRACTION99.23
Refinement TLS params.Method: refined / Origin x: 17.6247994906 Å / Origin y: 28.7858080706 Å / Origin z: 43.989688343 Å
111213212223313233
T0.156099642959 Å2-0.005933220329 Å2-0.0194936642874 Å2-0.166941263779 Å20.000108096489047 Å2--0.227779747374 Å2
L0.161738071506 °20.0140959735845 °2-0.0899241085922 °2-0.432720193387 °2-0.0576602543819 °2--0.814707897525 °2
S-0.00862595026385 Å °0.00881136453756 Å °-0.0131427282637 Å °0.0123800400848 Å °0.0405544510393 Å °-0.000861884531748 Å °0.0410369978726 Å °0.0116161768668 Å °-0.0271990161526 Å °
Refinement TLS groupSelection details: all

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