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

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Basic information

Entry
Database: PDB / ID: 6ulj
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 / Beta-lactamase/transpeptidase-like / Ankyrin repeat-containing domain superfamily
Similarity search - Domain/homology
Chem-QAA / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 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 UPGL00045
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 8, 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)233,1436
Polymers232,0964
Non-polymers1,0472
Water3,279182
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10920 Å2
ΔGint-42 kcal/mol
Surface area61220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.550, 138.888, 176.993
Angle α, β, γ (deg.)90.000, 93.914, 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-QAA / 2-phenyl-N-{6-[4-({6-[(phenylacetyl)amino]pyridazin-3-yl}oxy)piperidin-1-yl]pyridazin-3-yl}acetamide


Mass: 523.586 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H29N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 182 / 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: 3.33 Å3/Da / Density % sol: 63.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 12% PEG6000, 1.0M LiCl, pH 8.0 / 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 29, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.69→50 Å / Num. obs: 56593 / % possible obs: 85.8 % / Redundancy: 3.2 % / Biso Wilson estimate: 40.6 Å2 / Rrim(I) all: 0.131 / Rsym value: 0.101 / Net I/σ(I): 15.64
Reflection shellResolution: 2.7→2.75 Å / Redundancy: 2.6 % / Mean I/σ(I) obs: 2.8 / Num. unique obs: 2566 / CC1/2: 0.739 / Rrim(I) all: 0.597 / Rsym value: 0.425 / % possible all: 76.4

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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: 2.69→36.39 Å / SU ML: 0.3126 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.4426
RfactorNum. reflection% reflection
Rfree0.2363 2010 3.55 %
Rwork0.1785 --
obs0.1805 56556 85.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 47.92 Å2
Refinement stepCycle: LAST / Resolution: 2.69→36.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12772 0 78 182 13032
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009513146
X-RAY DIFFRACTIONf_angle_d1.361517741
X-RAY DIFFRACTIONf_chiral_restr0.06761938
X-RAY DIFFRACTIONf_plane_restr0.00792287
X-RAY DIFFRACTIONf_dihedral_angle_d10.29877871
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.69-2.760.33031260.23863439X-RAY DIFFRACTION74.63
2.76-2.830.35661440.23923803X-RAY DIFFRACTION84.74
2.83-2.920.29591510.23213947X-RAY DIFFRACTION85.82
2.92-3.010.28321390.22313809X-RAY DIFFRACTION85.14
3.01-3.120.27831520.22883888X-RAY DIFFRACTION85.27
3.12-3.240.26441390.21083884X-RAY DIFFRACTION86.02
3.24-3.390.27751370.19993908X-RAY DIFFRACTION85.79
3.39-3.570.24151560.18523913X-RAY DIFFRACTION85.68
3.57-3.790.22881400.16563887X-RAY DIFFRACTION85.25
3.79-4.090.20751440.15463863X-RAY DIFFRACTION84.89
4.09-4.50.17181390.1413856X-RAY DIFFRACTION84.35
4.5-5.150.20421370.13823846X-RAY DIFFRACTION84.89
5.15-6.480.22241460.18174015X-RAY DIFFRACTION87.36
6.48-36.390.21221600.16264488X-RAY DIFFRACTION96.33
Refinement TLS params.Method: refined / Origin x: -7.41749544707 Å / Origin y: -32.6851654195 Å / Origin z: 43.8672889187 Å
111213212223313233
T0.152192398052 Å20.00458215067196 Å2-0.00758851449263 Å2-0.156958976977 Å20.00698585829759 Å2--0.256071824636 Å2
L0.217827900623 °2-0.00903398745777 °2-0.0355040450547 °2-0.445752181751 °2-0.0497277871243 °2--1.10752066206 °2
S-0.0103382508208 Å °0.00980806976298 Å °0.00320156821069 Å °-0.00370993500527 Å °0.0629422196059 Å °-0.025795465671 Å °-0.00622403177458 Å °0.0143971768958 Å °-0.048732903685 Å °
Refinement TLS groupSelection details: all

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