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- PDB-6uk6: Crystal structure of human GAC in complex with inhibitor UPGL00018 -

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Basic information

Entry
Database: PDB / ID: 6uk6
TitleCrystal structure of human GAC in complex with inhibitor UPGL00018
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-Q9S / 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 UPGL00018
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 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)232,6956
Polymers232,0964
Non-polymers5992
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10590 Å2
ΔGint-46 kcal/mol
Surface area63730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.438, 138.790, 179.053
Angle α, β, γ (deg.)90.000, 89.987, 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

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PROPROLEULEU(chain 'A' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))AA137 - 18466 - 113
12VALVALALAALA(chain 'A' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))AA193 - 247122 - 176
13PROPROARGARG(chain 'A' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))AA258 - 544187 - 473
24PROPROLEULEU(chain 'B' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))BB137 - 18466 - 113
25VALVALALAALA(chain 'B' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))BB193 - 247122 - 176
26PROPROARGARG(chain 'B' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))BB258 - 544187 - 473
37PROPROLEULEU(chain 'C' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))CC137 - 18466 - 113
38VALVALALAALA(chain 'C' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))CC193 - 247122 - 176
39PROPROARGARG(chain 'C' and (resid 137 through 185 or resid 193 through 248 or resid 258 through 545))CC258 - 544187 - 473
410PROPROLEULEU(chain 'D' and (resid 137 through 248 or resid 258 through 545))DD137 - 18466 - 113
411VALVALALAALA(chain 'D' and (resid 137 through 248 or resid 258 through 545))DD193 - 247122 - 176
412PROPROARGARG(chain 'D' and (resid 137 through 248 or resid 258 through 545))DD258 - 544187 - 473

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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-Q9S / 5-{4-[(5-amino-1,3,4-thiadiazol-2-yl)oxy]piperidin-1-yl}-1,3,4-thiadiazol-2-amine


Mass: 299.376 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N7OS2 / 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: 3.79 Å3/Da / Density % sol: 67.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 12% PEG6000, 1.M LiCl, pH8.5 / 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: 2.7→50 Å / Num. obs: 71136 / % possible obs: 96.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 60.81 Å2 / Rrim(I) all: 0.163 / Rsym value: 0.138 / Net I/σ(I): 11.21
Reflection shellResolution: 2.7→2.75 Å / Redundancy: 2.6 % / Mean I/σ(I) obs: 0.146 / Num. unique obs: 3135 / CC1/2: 0.523 / Rsym value: 0.828 / % possible all: 84.4

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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: 2.9→22.05 Å / SU ML: 0.4914 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 41.2639
RfactorNum. reflection% reflection
Rfree0.3077 1603 2.84 %
Rwork0.2392 --
obs0.2412 56353 95.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 98.27 Å2
Refinement stepCycle: LAST / Resolution: 2.9→22.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12486 0 38 0 12524
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012412803
X-RAY DIFFRACTIONf_angle_d1.862817270
X-RAY DIFFRACTIONf_chiral_restr0.09011890
X-RAY DIFFRACTIONf_plane_restr0.01122225
X-RAY DIFFRACTIONf_dihedral_angle_d13.80547697
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.990.5871480.45324969X-RAY DIFFRACTION95.43
2.99-3.10.45211500.42874932X-RAY DIFFRACTION95.89
3.1-3.220.44831460.36824986X-RAY DIFFRACTION95.78
3.22-3.370.38861420.32294951X-RAY DIFFRACTION95.57
3.37-3.550.28351420.28874806X-RAY DIFFRACTION93.31
3.55-3.770.38251440.264850X-RAY DIFFRACTION93.57
3.77-4.060.32721430.23084802X-RAY DIFFRACTION92.76
4.06-4.460.32051470.19755013X-RAY DIFFRACTION95.86
4.46-5.10.20841410.18545073X-RAY DIFFRACTION97.66
5.1-6.40.29141530.19985200X-RAY DIFFRACTION99.85
6.4-22.050.21021470.16645168X-RAY DIFFRACTION97.24
Refinement TLS params.Method: refined / Origin x: -4.37265768196 Å / Origin y: -29.5557347945 Å / Origin z: 44.7611071812 Å
111213212223313233
T0.182880419882 Å20.00151407368272 Å2-0.0126878905194 Å2-0.494782516496 Å2-0.00648704887203 Å2--0.640110277036 Å2
L0.225330672563 °2-0.0113661038719 °2-0.00408265883214 °2-1.31664373212 °2-0.0882002182431 °2--2.52263267609 °2
S-0.0527040871543 Å °-0.000100351407529 Å °-0.00772762013627 Å °0.00857394600298 Å °0.233498351096 Å °-0.0360519263368 Å °-0.00729053560936 Å °-0.0100429648235 Å °-0.169685924867 Å °
Refinement TLS groupSelection details: all

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