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

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Basic information

Entry
Database: PDB / ID: 6ukb
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 / 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-Q9V / 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 UPGL00020
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: 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.
#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 4, 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)232,8636
Polymers232,0964
Non-polymers7672
Water00
1
B: Glutaminase kidney isoform, mitochondrial
D: Glutaminase kidney isoform, mitochondrial
hetero molecules

C: Glutaminase kidney isoform, mitochondrial

A: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)232,8636
Polymers232,0964
Non-polymers7672
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1/2,-y,z+1/21
crystal symmetry operation4_445x-1/2,-y-1/2,-z1
Buried area10430 Å2
ΔGint-43 kcal/mol
Surface area61880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.227, 139.393, 178.131
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
22chain 'B'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-Q9V / N-[5-(4-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]oxy}piperidin-1-yl)-1,3,4-thiadiazol-2-yl]acetamide


Mass: 383.449 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H17N7O3S2 / 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: 2.65 Å3/Da / Density % sol: 53.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 12% PEG6000, 1.0M 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: 3→50 Å / Num. obs: 50186 / % possible obs: 99.7 % / Redundancy: 7.9 % / Biso Wilson estimate: 51.11 Å2 / Rrim(I) all: 0.234 / Rsym value: 0.173 / Net I/σ(I): 13.54
Reflection shellResolution: 3→3.05 Å / Redundancy: 7.4 % / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2448 / CC1/2: 0.86 / Rsym value: 0.829 / % possible all: 99.4

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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→46.74 Å / SU ML: 0.3053 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.5474
RfactorNum. reflection% reflection
Rfree0.2503 1988 3.99 %
Rwork0.1945 --
obs0.1968 49811 99.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 55.88 Å2
Refinement stepCycle: LAST / Resolution: 3→46.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12768 0 50 0 12818
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009813110
X-RAY DIFFRACTIONf_angle_d1.180717696
X-RAY DIFFRACTIONf_chiral_restr0.06551938
X-RAY DIFFRACTIONf_plane_restr0.00772282
X-RAY DIFFRACTIONf_dihedral_angle_d6.7967862
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.080.36251380.27533331X-RAY DIFFRACTION98.89
3.08-3.160.37341400.2693376X-RAY DIFFRACTION99.35
3.16-3.250.31091410.24423381X-RAY DIFFRACTION99.18
3.25-3.360.31871410.2273363X-RAY DIFFRACTION99.15
3.36-3.480.27791390.22283376X-RAY DIFFRACTION99.13
3.48-3.620.24271420.20693378X-RAY DIFFRACTION99.52
3.62-3.780.241410.18743408X-RAY DIFFRACTION99.33
3.78-3.980.27731420.18573418X-RAY DIFFRACTION99.58
3.98-4.230.22691410.17473398X-RAY DIFFRACTION99.83
4.23-4.550.21561440.16483428X-RAY DIFFRACTION99.69
4.55-5.010.22041440.16053455X-RAY DIFFRACTION99.67
5.01-5.740.25841410.18183450X-RAY DIFFRACTION99.75
5.74-7.220.2611460.20443506X-RAY DIFFRACTION99.84
7.22-46.740.18851480.17253555X-RAY DIFFRACTION96.94
Refinement TLS params.Method: refined / Origin x: -17.8559213261 Å / Origin y: -14.7852902399 Å / Origin z: -36.4211667678 Å
111213212223313233
T0.28986405963 Å20.0124297411992 Å20.0281635947776 Å2-0.255972212132 Å2-0.014607711745 Å2--0.237200911912 Å2
L0.046073657635 °20.05809134299 °20.0105526572853 °2-0.320763783682 °2-0.266003385578 °2--0.150717163276 °2
S-0.00357835516329 Å °0.0229828937725 Å °-0.00538011970267 Å °-0.0255589563039 Å °0.0390365500955 Å °0.0568266420219 Å °-0.022371528571 Å °-0.0196431450326 Å °-0.0341759884261 Å °
Refinement TLS groupSelection details: all

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