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- PDB-6hvj: Human PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 3 -

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Basic information

Entry
Database: PDB / ID: 6hvj
TitleHuman PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 3
Components6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3
KeywordsTRANSFERASE / kinase / complex / metabolism / cancer
Function / homology
Function and homology information


6-phosphofructo-2-kinase / 6-phosphofructo-2-kinase activity / fructose 2,6-bisphosphate metabolic process / fructose-2,6-bisphosphate 2-phosphatase / fructose-2,6-bisphosphate 2-phosphatase activity / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / fructose metabolic process / nucleoplasm / ATP binding / cytosol
Similarity search - Function
Fructose-2,6-bisphosphatase / 6-phosphofructo-2-kinase / 6-phosphofructo-2-kinase / Phosphoglycerate/bisphosphoglycerate mutase, active site / Phosphoglycerate mutase family phosphohistidine signature. / Phosphoglycerate mutase family / Phosphoglycerate mutase-like / Histidine phosphatase superfamily, clade-1 / Histidine phosphatase superfamily (branch 1) / Histidine phosphatase superfamily ...Fructose-2,6-bisphosphatase / 6-phosphofructo-2-kinase / 6-phosphofructo-2-kinase / Phosphoglycerate/bisphosphoglycerate mutase, active site / Phosphoglycerate mutase family phosphohistidine signature. / Phosphoglycerate mutase family / Phosphoglycerate mutase-like / Histidine phosphatase superfamily, clade-1 / Histidine phosphatase superfamily (branch 1) / Histidine phosphatase superfamily / P-loop containing nucleotide triphosphate hydrolases / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
6-O-phosphono-beta-D-fructofuranose / CITRATE ANION / Chem-GV8 / PHOSPHATE ION / 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.28 Å
AuthorsBanaszak, K. / Pawlik, H. / Bialas, A. / Fabritius, C.H. / Nowak, M.
Funding support1items
OrganizationGrant numberCountry
European Regional Development FundPOIG.01.04.00-12-120/12-00
CitationJournal: ChemMedChem / Year: 2019
Title: Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.
Authors: Boutard, N. / Bialas, A. / Sabiniarz, A. / Guzik, P. / Banaszak, K. / Biela, A. / Bien, M. / Buda, A. / Bugaj, B. / Cieluch, E. / Cierpich, A. / Dudek, L. / Eggenweiler, H.M. / Fogt, J. / ...Authors: Boutard, N. / Bialas, A. / Sabiniarz, A. / Guzik, P. / Banaszak, K. / Biela, A. / Bien, M. / Buda, A. / Bugaj, B. / Cieluch, E. / Cierpich, A. / Dudek, L. / Eggenweiler, H.M. / Fogt, J. / Gaik, M. / Gondela, A. / Jakubiec, K. / Jurzak, M. / Kitlinska, A. / Kowalczyk, P. / Kujawa, M. / Kwiecinska, K. / Les, M. / Lindemann, R. / Maciuszek, M. / Mikulski, M. / Niedziejko, P. / Obara, A. / Pawlik, H. / Rzymski, T. / Sieprawska-Lupa, M. / Sowinska, M. / Szeremeta-Spisak, J. / Stachowicz, A. / Tomczyk, M.M. / Wiklik, K. / Wloszczak, L. / Ziemianska, S. / Zarebski, A. / Brzozka, K. / Nowak, M. / Fabritius, C.H.
History
DepositionOct 11, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 16, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.name
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,6695
Polymers59,6941
Non-polymers9754
Water2,126118
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1230 Å2
ΔGint-8 kcal/mol
Surface area20510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.129, 103.129, 254.438
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3


Mass: 59694.137 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: Q16875
#3: Sugar ChemComp-F6P / 6-O-phosphono-beta-D-fructofuranose / Fructose 6-phosphate


Type: D-saccharide, beta linking / Mass: 260.136 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C6H13O9P
IdentifierTypeProgram
b-D-Fruf6PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0

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Non-polymers , 4 types, 121 molecules

#2: Chemical ChemComp-GV8 / 8-(3-methyl-1-benzofuran-5-yl)-~{N}-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine


Mass: 430.479 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18N4O3S
#4: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-FLC / CITRATE ANION / Citric acid


Mass: 189.100 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H5O7
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 118 / Source method: isolated from a natural source / Formula: H2O

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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: 3.91 Å3/Da / Density % sol: 68.54 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 2% Tacsimate, pH 7.0; 5% 2-propanol; 0.1M imidazole; 8% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.28→47.79 Å / Num. obs: 37392 / % possible obs: 99.8 % / Redundancy: 10.523 % / Biso Wilson estimate: 49.429 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.103 / Rrim(I) all: 0.108 / Χ2: 0.912 / Net I/σ(I): 17.07
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.28-2.429.1820.9822.0958470.671.0498.8
2.42-2.5811.2740.6813.6255940.8780.713100
2.58-2.7910.7310.4415.4651920.9420.462100
2.79-3.0511.160.2519.648130.9820.263100
3.05-3.4110.6670.13816.2743900.9940.145100
3.41-3.9410.9160.07139030.9980.07499.9
3.94-4.8210.5180.04633580.9990.048100
4.82-6.7810.3450.04326690.9990.045100
6.78-47.799.1930.0316250.9990.03299.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.28→47.79 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.939 / SU B: 5.72 / SU ML: 0.135 / SU R Cruickshank DPI: 0.1935 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.194 / ESU R Free: 0.177
RfactorNum. reflection% reflectionSelection details
Rfree0.2385 1496 4 %RANDOM
Rwork0.2008 ---
obs0.2023 35895 99.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 139.05 Å2 / Biso mean: 45.682 Å2 / Biso min: 24.53 Å2
Baniso -1Baniso -2Baniso -3
1--0.3 Å2-0.15 Å2-0 Å2
2---0.3 Å2-0 Å2
3---0.96 Å2
Refinement stepCycle: final / Resolution: 2.28→47.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3506 0 65 118 3689
Biso mean--45.07 44.28 -
Num. residues----430
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0193638
X-RAY DIFFRACTIONr_bond_other_d0.0010.023422
X-RAY DIFFRACTIONr_angle_refined_deg1.5941.9814935
X-RAY DIFFRACTIONr_angle_other_deg0.7543.0027857
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9495433
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.44823.483178
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.44415637
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7511532
X-RAY DIFFRACTIONr_chiral_restr0.0860.2539
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214072
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02854
LS refinement shellResolution: 2.279→2.338 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.375 105 -
Rwork0.315 2535 -
all-2640 -
obs--97.45 %

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