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- PDB-4d4j: human PFKFB3 in complex with a pyrrolopyrimidone compound -

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Basic information

Entry
Database: PDB / ID: 4d4j
Titlehuman PFKFB3 in complex with a pyrrolopyrimidone compound
Components6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 3
KeywordsTRANSFERASE / SUGAR KINASE / WARBURG EFFECT / ONCOLOGY
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
Chem-BKI / 6-O-phosphono-beta-D-fructofuranose / PHOSPHONIC ACID / PHOSPHATE ION / 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsStgallay, S.A. / Bennett, N. / Critchlow, S. / Davies, G. / Debreczeni, J.E. / Evans, N. / Holdgate, G. / Jones, N.P. / Leach, L. / Maman, S. ...Stgallay, S.A. / Bennett, N. / Critchlow, S. / Davies, G. / Debreczeni, J.E. / Evans, N. / Holdgate, G. / Jones, N.P. / Leach, L. / Maman, S. / McLoughlin, S. / Preston, M. / Rigoreau, L. / Thomas, A. / Walker, G. / Walsch, J. / Ward, R.A. / Wheatley, E. / Winter, J.
CitationJournal: To be Published
Title: Identifying a Novel Series of Pfkfb3 Inhibitors as a Metabolic Approach to Treating Cancer from Hts, Biophysical and Biochemical Methods
Authors: Stgallay, S.A. / Bennett, N. / Critchlow, S. / Davies, G. / Debreczeni, J.E. / Evans, N. / Holdgate, G. / Jones, N.P. / Leach, L. / Maman, S. / Mcloughlin, S. / Preston, M. / Rigoreau, L. / ...Authors: Stgallay, S.A. / Bennett, N. / Critchlow, S. / Davies, G. / Debreczeni, J.E. / Evans, N. / Holdgate, G. / Jones, N.P. / Leach, L. / Maman, S. / Mcloughlin, S. / Preston, M. / Rigoreau, L. / Thomas, A. / Walker, G. / Walsch, J. / Ward, R.A. / Wheatley, E. / Winter, J.
History
DepositionOct 29, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / 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_database_status.status_code_sf / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2May 8, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
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)52,8705
Polymers52,0661
Non-polymers8034
Water2,126118
1
A: 6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 3
hetero molecules

A: 6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,74010
Polymers104,1332
Non-polymers1,6078
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_554x,x-y,-z-1/61
Buried area5830 Å2
ΔGint-40.9 kcal/mol
Surface area38820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.430, 102.430, 258.630
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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 / 6PF-2-K/FRU-2\ / 6-P2ASE 3 / PFKFBPASE 3 PFKFB3 / 6PF-2-K/FRU-2\ / 6-P2ASE BRAIN/PLACENTA-TYPE ...6PF-2-K/FRU-2\ / 6-P2ASE 3 / PFKFBPASE 3 PFKFB3 / 6PF-2-K/FRU-2\ / 6-P2ASE BRAIN/PLACENTA-TYPE ISOZYME / RENAL CARCINOMA ANTIGEN NY-REN-56 / IPFK-2 / 6-PHOSPHOFRUCTO-2-KINASE / FRUCTOSE-2\ / 6-BISPHOSPHATASE


Mass: 52066.453 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) / Strain (production host): BL21
References: UniProt: Q16875, 6-phosphofructo-2-kinase, fructose-2,6-bisphosphate 2-phosphatase
#4: 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, 121 molecules

#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-PHS / PHOSPHONIC ACID


Mass: 81.996 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: H3O3P
#5: Chemical ChemComp-BKI / 5-(4-bromophenyl)-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one


Mass: 366.211 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H12BrN3O
#6: Water ChemComp-HOH / 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: 3.76 Å3/Da / Density % sol: 67.3 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Feb 9, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 3→88.71 Å / Num. obs: 16896 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 18.8 % / Biso Wilson estimate: 73.62 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 24.5
Reflection shellResolution: 3→3.01 Å / Redundancy: 19.9 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 7 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→88.71 Å / Cor.coef. Fo:Fc: 0.9261 / Cor.coef. Fo:Fc free: 0.8814 / SU R Cruickshank DPI: 0.782 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.271 / SU Rfree Blow DPI: 0.297 / SU Rfree Cruickshank DPI: 0.291
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2069 856 5.09 %RANDOM
Rwork0.1897 ---
obs0.1905 16826 99.7 %-
Displacement parametersBiso mean: 55.78 Å2
Baniso -1Baniso -2Baniso -3
1--5.253 Å20 Å20 Å2
2---5.253 Å20 Å2
3---10.5061 Å2
Refine analyzeLuzzati coordinate error obs: 0.531 Å
Refinement stepCycle: LAST / Resolution: 3→88.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3534 0 48 118 3700
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083677HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.014993HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1288SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes91HARMONIC2
X-RAY DIFFRACTIONt_gen_planes558HARMONIC5
X-RAY DIFFRACTIONt_it3677HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion18.1
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion472SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4212SEMIHARMONIC4
LS refinement shellResolution: 3→3.21 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.3104 150 5.14 %
Rwork0.2239 2771 -
all0.2281 2921 -
obs--99.7 %
Refinement TLS params.Method: refined / Origin x: -30.5103 Å / Origin y: -27.971 Å / Origin z: -8.9173 Å
111213212223313233
T0.0064 Å20.0152 Å20.0061 Å2--0.1676 Å20.0607 Å2---0.1097 Å2
L1.0002 °20.1753 °2-0.0465 °2-0.9928 °2-0.4462 °2--1.2562 °2
S0.0262 Å °-0.0907 Å °-0.055 Å °0.2489 Å °-0.1337 Å °0.0236 Å °0.1016 Å °0.052 Å °0.1074 Å °
Refinement TLS groupSelection details: CHAIN A AND RESID 1-445

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