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

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Basic information

Entry
Database: PDB / ID: 6ula
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-QA4 / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 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 UPGL00030
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 7, 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
Revision 1.2Dec 25, 2024Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_validate_close_contact / struct_conn
Item: _pdbx_entry_details.has_protein_modification

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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
G: Glutaminase kidney isoform, mitochondrial
F: Glutaminase kidney isoform, mitochondrial
H: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)466,04612
Polymers464,1928
Non-polymers1,8544
Water00
1
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)233,0236
Polymers232,0964
Non-polymers9272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10600 Å2
ΔGint-45 kcal/mol
Surface area61020 Å2
MethodPISA
2
E: Glutaminase kidney isoform, mitochondrial
G: Glutaminase kidney isoform, mitochondrial
F: Glutaminase kidney isoform, mitochondrial
H: Glutaminase kidney isoform, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)233,0236
Polymers232,0964
Non-polymers9272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11520 Å2
ΔGint-45 kcal/mol
Surface area61090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.723, 138.888, 177.154
Angle α, β, γ (deg.)90.000, 89.984, 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
51
61
71
81

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
55chain 'E'EE
66(chain 'F' and resid 137 through 545)FG
77(chain 'G' and resid 137 through 545)GF
88(chain 'H' and resid 137 through 545)HH

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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 (E. coli) / References: UniProt: O94925, glutaminase
#2: Chemical
ChemComp-QA4 / 2-cyclopropyl-N-{5-[4-({5-[(cyclopropylacetyl)amino]-1,3,4-thiadiazol-2-yl}oxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}acetamide


Mass: 463.577 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H25N7O3S2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: 2.62 Å3/Da / Density % sol: 52.99 %
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: 2.7→50 Å / Num. obs: 124737 / % possible obs: 97.2 % / Redundancy: 3.3 % / Biso Wilson estimate: 51.9 Å2 / Rrim(I) all: 0.185 / Rsym value: 0.126 / Net I/σ(I): 9.14
Reflection shellResolution: 2.7→2.75 Å / Redundancy: 3.1 % / Num. unique obs: 6102 / CC1/2: 0.528 / Rsym value: 0.783 / % possible all: 95.7

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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: 2.95→37.89 Å / SU ML: 0.4504 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 36.6991
RfactorNum. reflection% reflection
Rfree0.2792 1570 1.61 %
Rwork0.2167 --
obs0.2177 97694 97.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 50.52 Å2
Refinement stepCycle: LAST / Resolution: 2.95→37.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms25544 0 124 0 25668
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011426260
X-RAY DIFFRACTIONf_angle_d1.488235450
X-RAY DIFFRACTIONf_chiral_restr0.06923884
X-RAY DIFFRACTIONf_plane_restr0.00934566
X-RAY DIFFRACTIONf_dihedral_angle_d11.39315758
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.95-3.050.43441390.34588457X-RAY DIFFRACTION94.38
3.05-3.150.41571320.30838555X-RAY DIFFRACTION95.02
3.15-3.280.3531390.28148512X-RAY DIFFRACTION95.13
3.28-3.430.32211410.26988552X-RAY DIFFRACTION95.83
3.43-3.610.26951450.23148732X-RAY DIFFRACTION97.23
3.61-3.840.28321450.21448802X-RAY DIFFRACTION97.78
3.84-4.130.26011430.20378802X-RAY DIFFRACTION98.02
4.13-4.550.23951430.18228876X-RAY DIFFRACTION98.89
4.55-5.20.26281490.17468954X-RAY DIFFRACTION99.09
5.2-6.550.2631450.20689015X-RAY DIFFRACTION99.77
6.55-37.890.22171490.17648867X-RAY DIFFRACTION96.89
Refinement TLS params.Method: refined / Origin x: -94.2458397172 Å / Origin y: 170.290129094 Å / Origin z: 44.3117755149 Å
111213212223313233
T0.349134478564 Å2-0.00318448798499 Å2-0.00194104794948 Å2-0.201193950836 Å2-5.43868605306E-5 Å2--0.297419675186 Å2
L0.1983668308 °2-0.00468182190115 °2-0.00264099261508 °2-0.246162417716 °20.0094886572549 °2--0.239303512999 °2
S-0.00131964330256 Å °-0.00285783554301 Å °-0.000450220598456 Å °0.00613811402703 Å °0.0273572286473 Å °0.0258495382631 Å °-0.00426620705226 Å °-0.00569450200632 Å °-0.0209166121815 Å °
Refinement TLS groupSelection details: all

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