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- PDB-6lox: Crystal Structure of human glutaminase with macrocyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 6lox
TitleCrystal Structure of human glutaminase with macrocyclic inhibitor
ComponentsGlutaminase kidney isoform, mitochondrial
KeywordsPROTEIN BINDING / protein-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 / Ankyrin repeat-containing domain superfamily / Beta-lactamase/transpeptidase-like
Similarity search - Domain/homology
Chem-EN3 / Glutaminase kidney isoform, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsBian, J. / Li, Z. / Xu, X. / Wang, J. / Li, L.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81703347 China
National Natural Science Foundation of China (NSFC)81872746 China
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site.
Authors: Xu, X. / Wang, J. / Wang, M. / Yuan, X. / Li, L. / Zhang, C. / Huang, H. / Jing, T. / Wang, C. / Tong, C. / Zhou, L. / Meng, Y. / Xu, P. / Kou, J. / Qiu, Z. / Li, Z. / Bian, J.
History
DepositionJan 7, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: 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 / 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)236,9496
Polymers235,7524
Non-polymers1,1972
Water23413
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9480 Å2
ΔGint-38 kcal/mol
Surface area58060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.974, 138.673, 177.669
Angle α, β, γ (deg.)90.000, 94.160, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEUGLUGLUAA139 - 54569 - 475
21LEULEUGLUGLUBB139 - 54569 - 475
12LEULEUARGARGAA139 - 54469 - 474
22LEULEUARGARGCC139 - 54469 - 474
13LEULEUGLUGLUAA139 - 54569 - 475
23LEULEUGLUGLUDD139 - 54569 - 475
14LEULEUARGARGBB139 - 54469 - 474
24LEULEUARGARGCC139 - 54469 - 474
15LEULEUGLUGLUBB139 - 54569 - 475
25LEULEUGLUGLUDD139 - 54569 - 475
16PROPROGLUGLUCC137 - 54567 - 475
26PROPROGLUGLUDD137 - 54567 - 475

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 58937.992 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLS, GLS1, KIAA0838 / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O94925, glutaminase
#2: Chemical ChemComp-EN3 / (E)-15,22-Dioxa-4,11-diaza-5(2,5)-thiadiazola-10(3,6)-pyridazina-1,14(1,3)-dibenzenacyclodocosaphan-18-ene-3,12-dione


Mass: 598.715 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H34N6O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 2.6 Å3/Da / Density % sol: 52.77 % / Mosaicity: 0.29 °
Crystal growTemperature: 289 K / Method: evaporation / pH: 8.7 / Details: PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 3.2→47.14 Å / Num. obs: 39470 / % possible obs: 98.9 % / Redundancy: 3.8 % / CC1/2: 0.991 / Rmerge(I) obs: 0.15 / Rpim(I) all: 0.088 / Rrim(I) all: 0.175 / Net I/σ(I): 8.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.2-3.3340.5911804645260.8940.3350.6822.499.4
11.54-47.13.80.03332058530.9980.0190.03927.994.9

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3UO9

3uo9


Resolution: 3.2→47.14 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.897 / Rfactor Rfree error: 0.491 / SU B: 32.658 / SU ML: 0.491 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.483 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2603 1936 4.9 %RANDOM
Rwork0.2219 ---
obs0.2238 37472 98.63 %-
Solvent computationIon probe radii: 0.9 Å / Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å
Displacement parametersBiso max: 201.29 Å2 / Biso mean: 61.869 Å2 / Biso min: 18.7 Å2
Baniso -1Baniso -2Baniso -3
1-13.95 Å20 Å2-2.45 Å2
2---6.28 Å20 Å2
3----7.24 Å2
Refinement stepCycle: final / Resolution: 3.2→47.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11990 0 86 13 12089
Biso mean--86.18 34.49 -
Num. residues----1629
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01212362
X-RAY DIFFRACTIONr_angle_refined_deg1.5291.63716799
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.99851623
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.85723.245530
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.765151789
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2381539
X-RAY DIFFRACTIONr_chiral_restr0.1090.21631
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.029549
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A128450.09
12B128450.09
21A129970.09
22C129970.09
31A127890.08
32D127890.08
41B128380.1
42C128380.1
51B128030.07
52D128030.07
61C127480.09
62D127480.09
LS refinement shellResolution: 3.2→3.283 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.348 175 -
Rwork0.343 2780 -
all-2955 -
obs--99.46 %

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