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- PDB-5ajy: Human PFKFB3 in complex with an indole inhibitor 4 -

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Basic information

Entry
Database: PDB / ID: 5ajy
TitleHuman PFKFB3 in complex with an indole inhibitor 4
Components6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 3
KeywordsTRANSFERASE
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-87T / 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: 2.37 Å
AuthorsBoyd, S. / Brookfield, J.L. / Critchlow, S.E. / Cumming, I.A. / Curtis, N.J. / Debreczeni, J.E. / Degorce, S.L. / Donald, C. / Evans, N.J. / Groombridge, S. ...Boyd, S. / Brookfield, J.L. / Critchlow, S.E. / Cumming, I.A. / Curtis, N.J. / Debreczeni, J.E. / Degorce, S.L. / Donald, C. / Evans, N.J. / Groombridge, S. / Hopcroft, P. / Jones, N.P. / Kettle, J.G. / Lamont, S. / Lewis, H.J. / MacFaull, P. / McLoughlin, S.B. / Rigoreau, L.J.M. / Smith, J.M. / St-Gallay, S. / Stock, J.K. / Wheatley, E.R. / Winter, J. / Wingfield, J.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase Pfkfb3.
Authors: Boyd, S. / Brookfield, J.L. / Critchlow, S.E. / Cumming, I.A. / Curtis, N.J. / Debreczeni, J. / Degorce, S.L. / Donald, C. / Evans, N.J. / Groombridge, S. / Hopcroft, P. / Jones, N.P. / ...Authors: Boyd, S. / Brookfield, J.L. / Critchlow, S.E. / Cumming, I.A. / Curtis, N.J. / Debreczeni, J. / Degorce, S.L. / Donald, C. / Evans, N.J. / Groombridge, S. / Hopcroft, P. / Jones, N.P. / Kettle, J.G. / Lamont, S. / Lewis, H.J. / Macfaull, P. / Mcloughlin, S.B. / Rigoreau, L.J.M. / Smith, J.M. / St-Gallay, S. / Stock, J.K. / Turnbull, A.P. / Wheatley, E.R. / Winter, J. / Wingfield, J.
History
DepositionFeb 27, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 22, 2015Provider: repository / Type: Initial release
Revision 1.1May 13, 2015Group: Database references
Revision 1.2Jul 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 1.3May 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)60,4935
Polymers59,6941
Non-polymers7984
Water2,090116
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)120,98510
Polymers119,3882
Non-polymers1,5978
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_554x,x-y,-z-1/61
Buried area5920 Å2
ΔGint-37.7 kcal/mol
Surface area38160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.817, 102.817, 261.793
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-2048-

HOH

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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 / PFK/FBPASE 3 / PFKFB3 / 6PF-2-K/FRU-2 / 6-P2ASE BRAIN/PLACENTA-TYPE ...6PF-2-K/FRU-2 / 6-P2ASE 3 / PFK/FBPASE 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: 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) / 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, 119 molecules

#2: Chemical ChemComp-PHS / PHOSPHONIC ACID


Mass: 81.996 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: H3O3P
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-87T / N-(4-{[3-(1-methyl-1H-pyrazol-4-yl)-1H-indol-5-yl]oxy}phenyl)glycinamide


Mass: 361.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19N5O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 3.35 Å3/Da / Density % sol: 64 % / Description: NONE
Crystal growDetails: 0.2M SODIUM MALONATE, 18W/V% PEG3350 AND 0.1 M PCTP BUFFER PH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Type: DIAMOND / Wavelength: 0.97972
DetectorType: DECTRIS PILATUS / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97972 Å / Relative weight: 1
ReflectionResolution: 2.37→37.4 Å / Num. obs: 37160 / % possible obs: 99.7 % / Observed criterion σ(I): 2 / Redundancy: 7 % / Biso Wilson estimate: 68.16 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 14.5
Reflection shellResolution: 2.37→2.45 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.99 / Mean I/σ(I) obs: 1.9 / % 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: 2.37→36.81 Å / Cor.coef. Fo:Fc: 0.9488 / Cor.coef. Fo:Fc free: 0.9379 / SU R Cruickshank DPI: 0.204 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.211 / SU Rfree Blow DPI: 0.166 / SU Rfree Cruickshank DPI: 0.165
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2119 1723 5.06 %RANDOM
Rwork0.1981 ---
obs0.1988 34066 99.7 %-
Displacement parametersBiso mean: 67.57 Å2
Baniso -1Baniso -2Baniso -3
1--0.9896 Å20 Å20 Å2
2---0.9896 Å20 Å2
3---1.9793 Å2
Refine analyzeLuzzati coordinate error obs: 0.373 Å
Refinement stepCycle: LAST / Resolution: 2.37→36.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3491 0 52 116 3659
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0093637HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.024945HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1260SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes88HARMONIC2
X-RAY DIFFRACTIONt_gen_planes529HARMONIC5
X-RAY DIFFRACTIONt_it3637HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.07
X-RAY DIFFRACTIONt_other_torsion18.35
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion471SEMIHARMONIC5
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_contact4103SEMIHARMONIC4
LS refinement shellResolution: 2.37→2.44 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2528 150 5.18 %
Rwork0.2438 2748 -
all0.2442 2898 -
obs--99.7 %
Refinement TLS params.Method: refined / Origin x: -30.8244 Å / Origin y: -28.0935 Å / Origin z: -9.0873 Å
111213212223313233
T-0.1065 Å2-0.014 Å20.0295 Å2--0.3259 Å20.0132 Å2---0.3042 Å2
L0.8374 °20.1137 °2-0.0332 °2-1.1784 °2-0.1143 °2--1.1888 °2
S0.0497 Å °-0.0603 Å °-0.0732 Å °0.3847 Å °-0.1363 Å °0.0864 Å °0.2804 Å °-0.0158 Å °0.0866 Å °
Refinement TLS groupSelection details: CHAIN A

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