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- PDB-6ibz: Human PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 7 -

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Basic information

Entry
Database: PDB / ID: 6ibz
TitleHuman PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 7
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 / 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-HAW / 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: 2.44 Å
AuthorsBanaszak, K. / Tomczyk, M. / Guzik, P. / Fabritius, C.H. / Nowak, M.
Funding support1items
OrganizationGrant numberCountry
European Regional Development FundPOIG.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)51,2085
Polymers50,1421
Non-polymers1,0664
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1230 Å2
ΔGint-9 kcal/mol
Surface area20430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.046, 103.046, 253.938
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: 50142.145 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 , 4 types, 129 molecules

#2: Chemical ChemComp-PO4 / PHOSPHATE ION


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


Mass: 189.100 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H5O7
#4: Chemical ChemComp-HAW / 2-[[8-(1-methylindol-6-yl)quinoxalin-6-yl]amino]-~{N}-(pyrimidin-5-ylmethyl)benzenesulfonamide


Mass: 521.593 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H23N7O2S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / 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: 3.88 Å3/Da / Density % sol: 68.31 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 2% Tacsimate, pH7.0; 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: Jul 6, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.44→47.74 Å / Num. obs: 30561 / % possible obs: 99.9 % / Redundancy: 10.683 % / Biso Wilson estimate: 44.58 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.153 / Rrim(I) all: 0.161 / Χ2: 0.897 / Net I/σ(I): 13.84 / Num. measured all: 326477
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.44-2.5910.8070.9282.5948020.7210.97599.5
2.59-2.7710.7720.6923.4745280.8440.726100
2.77-2.9911.1390.4575.3242520.9350.479100
2.99-3.2710.5480.2957.8939280.9730.31100
3.27-3.6510.9980.15114.9535950.9930.158100
3.65-4.2110.5950.0931780.9970.095100
4.21-5.1510.7810.06427560.9990.067100
5.15-7.2410.050.06521810.9980.069100
7.24-47.749.0740.03613410.9990.03899.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3QPU

3qpu


Resolution: 2.44→47.74 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.926 / SU B: 7.086 / SU ML: 0.156 / SU R Cruickshank DPI: 0.2408 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.241 / ESU R Free: 0.206
RfactorNum. reflection% reflectionSelection details
Rfree0.2335 1223 4 %RANDOM
Rwork0.1924 ---
obs0.194 29337 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 144.13 Å2 / Biso mean: 42.094 Å2 / Biso min: 15.64 Å2
Baniso -1Baniso -2Baniso -3
1--0.25 Å2-0.13 Å2-0 Å2
2---0.25 Å2-0 Å2
3---0.82 Å2
Refinement stepCycle: final / Resolution: 2.44→47.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3510 0 72 126 3708
Biso mean--41.73 39.22 -
Num. residues----431
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193660
X-RAY DIFFRACTIONr_bond_other_d0.0010.023445
X-RAY DIFFRACTIONr_angle_refined_deg1.5171.9854959
X-RAY DIFFRACTIONr_angle_other_deg0.7353.0027917
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9025431
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.52123.556180
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.18315647
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8371532
X-RAY DIFFRACTIONr_chiral_restr0.0770.2538
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214087
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02859
LS refinement shellResolution: 2.44→2.503 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 88 -
Rwork0.278 2097 -
all-2185 -
obs--99 %

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