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

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Basic information

Entry
Database: PDB / ID: 6umd
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-QAJ / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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 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.A. / 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. / Reimer, S. / Sun, J. / Boby, M. / Yang, T. / Fioravanti, M. / O'Neill, J. / Wang, L. / Drakes, D. / Katt, W.P. / Huang, Q. / Cerione, R.A.
#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 9, 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)233,2816
Polymers232,2084
Non-polymers1,0732
Water75742
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)233,2816
Polymers232,2084
Non-polymers1,0732
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x+1/2,-y,z-1/21
crystal symmetry operation4_455x-1/2,-y+1/2,-z1
Buried area10910 Å2
ΔGint-42 kcal/mol
Surface area61660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.477, 139.161, 178.186
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
12PHEPHEARGARGchain 'A'AA256 - 544185 - 473
23PROPROASPASP(chain 'B' and (resid 137 through 249 or resid 256 through 545))BB137 - 24866 - 177
24PHEPHEARGARG(chain 'B' and (resid 137 through 249 or resid 256 through 545))BB256 - 544185 - 473
35PROPROASPASP(chain 'C' and (resid 137 through 249 or resid 256 through 545))CC137 - 24866 - 177
36PHEPHEARGARG(chain 'C' and (resid 137 through 249 or resid 256 through 545))CC256 - 544185 - 473
47PROPROASPASP(chain 'D' and (resid 137 through 249 or resid 256 through 545))DD137 - 24866 - 177
48PHEPHEARGARG(chain 'D' and (resid 137 through 249 or resid 256 through 545))DD256 - 544185 - 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-QAJ / 2-(pyridin-3-yl)-N-(5-{4-[(5-{[(pyridin-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)amino]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)acetamide


Mass: 536.632 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N10O2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 2.68 Å3/Da / Density % sol: 54.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 12% PEG6000, 1.0 M LiCl pH 8.0 / 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 28, 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: 85958 / % possible obs: 98.2 % / Redundancy: 6.8 % / Biso Wilson estimate: 47.33 Å2 / Rrim(I) all: 0.144 / Rsym value: 0.096 / Net I/σ(I): 15.72
Reflection shellResolution: 2.5→2.54 Å / Redundancy: 6 % / Mean I/σ(I) obs: 1.59 / Num. unique obs: 3800 / CC1/2: 0.903 / Rsym value: 0.519 / % possible all: 88.6

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Processing

Software
NameVersionClassification
PHENIX1.17_3644refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d3o

5d3o


Resolution: 2.7→20.23 Å / SU ML: 0.3552 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 40.3441
RfactorNum. reflection% reflection
Rfree0.2876 1586 2.33 %
Rwork0.2278 --
obs0.2292 68182 98.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 65.51 Å2
Refinement stepCycle: LAST / Resolution: 2.7→20.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12726 0 74 42 12842
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011713094
X-RAY DIFFRACTIONf_angle_d1.625717672
X-RAY DIFFRACTIONf_chiral_restr0.08531932
X-RAY DIFFRACTIONf_plane_restr0.00972272
X-RAY DIFFRACTIONf_dihedral_angle_d15.40711816
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.790.39171420.3365961X-RAY DIFFRACTION98.15
2.79-2.890.3541390.30745969X-RAY DIFFRACTION98.76
2.89-30.45221440.2955990X-RAY DIFFRACTION99.03
3-3.140.33251440.27866020X-RAY DIFFRACTION98.62
3.14-3.30.31371430.26696013X-RAY DIFFRACTION98.76
3.3-3.510.29061430.24246005X-RAY DIFFRACTION98.91
3.51-3.780.27071430.2126068X-RAY DIFFRACTION99.17
3.78-4.150.27921470.20266074X-RAY DIFFRACTION99.17
4.15-4.750.23921460.18236117X-RAY DIFFRACTION99.13
4.75-5.960.28431470.20726185X-RAY DIFFRACTION99.4
5.96-20.230.22611480.20516194X-RAY DIFFRACTION96.46
Refinement TLS params.Method: refined / Origin x: 32.2008828855 Å / Origin y: 14.9818841114 Å / Origin z: 36.3555504784 Å
111213212223313233
T0.436895138813 Å2-0.00544595583397 Å2-0.031487819813 Å2-0.440790986544 Å2-0.0258797915525 Å2--0.475324052026 Å2
L0.0182292362341 °2-0.0115495865086 °2-0.0453791963545 °2-0.384536790045 °2-0.409230724924 °2--0.3878773809 °2
S-0.00873585971111 Å °-0.0304776539202 Å °0.00453225662217 Å °0.0242993107365 Å °0.0922246465854 Å °0.0914587969584 Å °0.0445890297902 Å °-0.0810627431989 Å °-0.0920848936727 Å °
Refinement TLS groupSelection details: all

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