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- PDB-6ul9: Crystal structure of human GAC in complex with inhibitor UPGL00023 -

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Basic information

Entry
Database: PDB / ID: 6ul9
TitleCrystal structure of human GAC in complex with inhibitor UPGL00023
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-Q9M / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsHuang, Q.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. / 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_symm_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)233,2236
Polymers232,2084
Non-polymers1,0152
Water10,881604
1
B: Glutaminase kidney isoform, mitochondrial
D: Glutaminase kidney isoform, mitochondrial
hetero molecules

C: Glutaminase kidney isoform, mitochondrial

A: Glutaminase kidney isoform, mitochondrial


Theoretical massNumber of molelcules
Total (without water)233,2236
Polymers232,2084
Non-polymers1,0152
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x+1/2,-y,z-1/21
crystal symmetry operation4_545x+1/2,-y-1/2,-z1
Buried area11150 Å2
ΔGint-50 kcal/mol
Surface area59610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.880, 138.235, 176.489
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

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PROPROASPASPchain 'A'AA137 - 24866 - 177
12SERSERARGARGchain 'A'AA257 - 544186 - 473
23PROPROASPASP(chain 'B' and (resid 137 through 249 or resid 257 through 545))BB137 - 24866 - 177
24SERSERARGARG(chain 'B' and (resid 137 through 249 or resid 257 through 545))BB257 - 544186 - 473
35PROPROASPASP(chain 'C' and (resid 137 through 249 or resid 257 through 545))CC137 - 24866 - 177
36SERSERARGARG(chain 'C' and (resid 137 through 249 or resid 257 through 545))CC257 - 544186 - 473
47PROPROASPASP(chain 'D' and (resid 137 through 249 or resid 257 through 545))DD137 - 24866 - 177
48SERSERARGARG(chain 'D' and (resid 137 through 249 or resid 257 through 545))DD257 - 544186 - 473

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Components

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


Mass: 58052.043 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-Q9M / 2-phenyl-N-{5-[(1-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}azetidin-3-yl)oxy]-1,3,4-thiadiazol-2-yl}acetamide


Mass: 507.588 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21N7O3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 604 / Source method: isolated from a natural source / Formula: H2O
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: 2.57 Å3/Da / Density % sol: 52.16 %
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 29, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 82779 / % possible obs: 99.6 % / Redundancy: 6.6 % / Biso Wilson estimate: 25.5 Å2 / Rsym value: 0.199 / Net I/σ(I): 16.23
Reflection shellResolution: 2.5→2.54 Å / Num. unique obs: 4060 / Rsym value: 0.473

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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: 2.5→48.94 Å / SU ML: 0.2829 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.4463
RfactorNum. reflection% reflection
Rfree0.2441 1999 2.42 %
Rwork0.1922 --
obs0.1935 82543 99.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 35.35 Å2
Refinement stepCycle: LAST / Resolution: 2.5→48.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12715 0 70 604 13389
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008913078
X-RAY DIFFRACTIONf_angle_d1.249817652
X-RAY DIFFRACTIONf_chiral_restr0.06161931
X-RAY DIFFRACTIONf_plane_restr0.00762276
X-RAY DIFFRACTIONf_dihedral_angle_d9.55767839
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.570.31291380.22245550X-RAY DIFFRACTION96.59
2.57-2.630.26651410.21475678X-RAY DIFFRACTION99.05
2.63-2.710.24651400.21895667X-RAY DIFFRACTION99.26
2.71-2.80.28861410.21025690X-RAY DIFFRACTION99.54
2.8-2.90.27551420.20975725X-RAY DIFFRACTION99.74
2.9-3.020.29481420.2095723X-RAY DIFFRACTION99.76
3.02-3.150.27611430.21735784X-RAY DIFFRACTION99.88
3.15-3.320.27041420.20765725X-RAY DIFFRACTION99.76
3.32-3.530.26081440.18855783X-RAY DIFFRACTION99.97
3.53-3.80.20041430.17255767X-RAY DIFFRACTION99.83
3.8-4.180.2391440.16855803X-RAY DIFFRACTION99.92
4.18-4.790.19621450.1615833X-RAY DIFFRACTION99.8
4.79-6.030.23691460.19115880X-RAY DIFFRACTION99.74
6.03-48.940.21291480.19155936X-RAY DIFFRACTION96.99
Refinement TLS params.Method: refined / Origin x: 17.7668999254 Å / Origin y: -14.8839361076 Å / Origin z: 35.9862163611 Å
111213212223313233
T0.193291824846 Å2-0.00219654493278 Å20.0203774575742 Å2-0.187104963434 Å20.0122396347729 Å2--0.178415537065 Å2
L0.0596856849998 °2-0.0210310187607 °20.014181802261 °2-0.273211713054 °20.222725692985 °2--0.145767648868 °2
S-0.00699974919905 Å °-0.0204673300385 Å °-0.00382313417778 Å °0.0427990484397 Å °0.0358100260318 Å °-0.0495835858265 Å °0.0143277234314 Å °0.0120393075528 Å °-0.0288630893604 Å °
Refinement TLS groupSelection details: all

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