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

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Basic information

Entry
Database: PDB / ID: 6ujg
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


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-Q9A / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 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 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
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
E: Glutaminase kidney isoform, mitochondrial
F: Glutaminase kidney isoform, mitochondrial
G: Glutaminase kidney isoform, mitochondrial
H: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)465,66612
Polymers464,1928
Non-polymers1,4744
Water00
1
A: Glutaminase kidney isoform, mitochondrial
C: Glutaminase kidney isoform, mitochondrial
F: Glutaminase kidney isoform, mitochondrial
H: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)232,8336
Polymers232,0964
Non-polymers7372
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10420 Å2
ΔGint-42 kcal/mol
Surface area61330 Å2
MethodPISA
2
B: Glutaminase kidney isoform, mitochondrial
D: Glutaminase kidney isoform, mitochondrial
E: Glutaminase kidney isoform, mitochondrial
G: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)232,8336
Polymers232,0964
Non-polymers7372
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10570 Å2
ΔGint-35 kcal/mol
Surface area60960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.828, 138.840, 177.207
Angle α, β, γ (deg.)90.000, 90.034, 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

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Components

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


Mass: 58023.996 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLS, GLS1, KIAA0838
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: O94925, glutaminase
#2: Chemical
ChemComp-Q9A / N-{5-[(3S)-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.: 4 / 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: 3.33 Å3/Da / Density % sol: 63.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 12% PEG6000, 1.0M LiCl, pH8.0 / PH range: 8.0-8.5

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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: 2.9→50 Å / Num. obs: 105300 / % possible obs: 98.5 % / Redundancy: 3.4 % / Biso Wilson estimate: 42.51 Å2 / CC1/2: 0.573 / Rrim(I) all: 0.293 / Rsym value: 0.188 / Net I/σ(I): 6.39
Reflection shellResolution: 2.9→2.95 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 0.982 / Num. unique obs: 5072 / Rsym value: 0.768 / % possible all: 95.8

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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: 3→34.94 Å / SU ML: 0.48 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 37.7842
RfactorNum. reflection% reflection
Rfree0.306 1777 1.9 %
Rwork0.2328 --
obs0.2342 93632 97.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 45.33 Å2
Refinement stepCycle: LAST / Resolution: 3→34.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms25552 0 96 0 25648
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009826232
X-RAY DIFFRACTIONf_angle_d1.156735408
X-RAY DIFFRACTIONf_chiral_restr0.05843876
X-RAY DIFFRACTIONf_plane_restr0.00734568
X-RAY DIFFRACTIONf_dihedral_angle_d7.004715728
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.080.47431320.35216843X-RAY DIFFRACTION95.76
3.08-3.170.3991330.2946964X-RAY DIFFRACTION96.53
3.17-3.270.31571360.27436975X-RAY DIFFRACTION97
3.27-3.390.35011310.27676983X-RAY DIFFRACTION97.43
3.39-3.530.3011420.26217086X-RAY DIFFRACTION98.49
3.53-3.690.33771400.23647139X-RAY DIFFRACTION98.9
3.69-3.880.33681380.23037123X-RAY DIFFRACTION99.17
3.88-4.120.27981420.22627110X-RAY DIFFRACTION98.53
4.12-4.440.30451390.20617127X-RAY DIFFRACTION98.99
4.44-4.890.27191330.19547102X-RAY DIFFRACTION97.93
4.89-5.590.27651380.2047174X-RAY DIFFRACTION99
5.59-7.040.31721400.22897264X-RAY DIFFRACTION99.54
7.04-34.940.22051330.18976965X-RAY DIFFRACTION94.59
Refinement TLS params.Method: refined / Origin x: 4.33421929934 Å / Origin y: -36.3803322488 Å / Origin z: 44.3068462356 Å
111213212223313233
T0.247557076051 Å20.00393635677147 Å2-0.0139655140337 Å2-0.153657169186 Å2-0.0112655848794 Å2--0.233912404208 Å2
L0.160632644581 °2-0.00285535900423 °2-0.007234326632 °2-0.316837998908 °20.0104230926917 °2--0.401896631399 °2
S0.033927388965 Å °0.00375770595873 Å °-0.00324563172078 Å °-0.0136130544151 Å °0.0453819885204 Å °0.0119494034313 Å °-0.00246694463019 Å °0.011040259843 Å °-0.0671446195821 Å °
Refinement TLS groupSelection details: all

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