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- PDB-6ibx: Human PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 5 -

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Basic information

Entry
Database: PDB / ID: 6ibx
TitleHuman PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 5
Components6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3
KeywordsTRANSFERASE / Cancer / Metabolism / Kinase / Inhibitor
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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
6-O-phosphono-beta-D-fructofuranose / CITRATE ANION / Chem-H9Z / PYROPHOSPHATE 2- / 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: 2.11 Å
AuthorsBanaszak, K. / Pawlik, H. / Bialas, A. / Fabritius, C.H. / Nowak, M.
Funding support1items
OrganizationGrant numberCountry
European Regional Development Fundunder The Operational Program Innovative Economy, 2007-2013, measure 1.4 (POIG.01.04.00-12-120/12-00)
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2019
Title: Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties.
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
DepositionDec 1, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 23, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 13, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
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
Revision 1.3Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)51,0846
Polymers49,8891
Non-polymers1,1955
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1550 Å2
ΔGint2 kcal/mol
Surface area19980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.782, 102.782, 254.440
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 / PFK/FBPase 3 / 6PF-2-K/Fru-2 / 6-P2ase brain/placenta-type isozyme / Renal carcinoma antigen NY-REN- ...PFK/FBPase 3 / 6PF-2-K/Fru-2 / 6-P2ase brain/placenta-type isozyme / Renal carcinoma antigen NY-REN-56 / iPFK-2


Mass: 49888.910 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PFKFB3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q16875, 6-phosphofructo-2-kinase, fructose-2,6-bisphosphate 2-phosphatase
#5: Sugar ChemComp-F6P / 6-O-phosphono-beta-D-fructofuranose / FRUCTOSE-6-PHOSPHATE / 6-O-phosphono-beta-D-fructose / 6-O-phosphono-D-fructose / 6-O-phosphono-fructose


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 , 5 types, 235 molecules

#2: Chemical ChemComp-H9Z / 3-[[8-(1-methylindol-6-yl)quinoxalin-6-yl]amino]-~{N}-[(3~{S})-1-methylpiperidin-3-yl]pyridine-4-carboxamide


Mass: 491.587 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H29N7O
#3: Chemical ChemComp-POP / PYROPHOSPHATE 2-


Mass: 175.959 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: H2O7P2
#4: Chemical ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H5O7
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 3.89 Å3/Da / Density % sol: 68.37 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 2% Tacsimate, 10% PEG3350, 0.1M MES/imidazole pH 7.0

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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: Aug 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.11→47.65 Å / Num. obs: 46675 / % possible obs: 99.6 % / Redundancy: 10.442 % / Biso Wilson estimate: 40.624 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.101 / Rrim(I) all: 0.107 / Χ2: 1.057 / Net I/σ(I): 19.26
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.11-2.239.370.9922.2772610.7441.04997.7
2.23-2.3911.0410.646469690.8980.677100
2.39-2.5810.5250.3916.3265120.960.411100
2.58-2.8211.20.269.7760270.9830.272100
2.82-3.1610.4690.14716.3554820.9930.155100
3.16-3.6410.8960.07848960.9980.081100
3.64-4.4510.1910.04441930.9990.047100
4.45-6.2710.1940.03433170.9990.036100
6.27-47.659.4420.026201810.02799.5

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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
Starting model: 3QPU

3qpu


Resolution: 2.11→47.65 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.939 / SU B: 4.257 / SU ML: 0.108 / SU R Cruickshank DPI: 0.1439 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.144 / ESU R Free: 0.137
RfactorNum. reflection% reflectionSelection details
Rfree0.2199 1867 4 %RANDOM
Rwork0.1871 ---
obs0.1884 44807 99.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 118.32 Å2 / Biso mean: 38.185 Å2 / Biso min: 20.29 Å2
Baniso -1Baniso -2Baniso -3
1--0.72 Å2-0.36 Å2-0 Å2
2---0.72 Å2-0 Å2
3---2.34 Å2
Refinement stepCycle: final / Resolution: 2.11→47.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3496 0 79 231 3806
Biso mean--36.97 44.86 -
Num. residues----429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0193664
X-RAY DIFFRACTIONr_bond_other_d0.0010.023459
X-RAY DIFFRACTIONr_angle_refined_deg1.5041.9864967
X-RAY DIFFRACTIONr_angle_other_deg0.7093.0047955
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8975433
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.01623.556180
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.54215649
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0891532
X-RAY DIFFRACTIONr_chiral_restr0.0840.2539
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0214085
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02856
LS refinement shellResolution: 2.107→2.161 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 128 -
Rwork0.304 3081 -
all-3209 -
obs--94.94 %

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