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- PDB-5ajv: Human PFKFB3 in complex with an indole inhibitor 1 -

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Basic information

Entry
Database: PDB / ID: 5ajv
TitleHuman PFKFB3 in complex with an indole inhibitor 1
ComponentsHUMAN PFKFB3
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-8R2 / 2,6-di-O-phosphono-beta-D-fructofuranose / 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: 3.01 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
B: HUMAN PFKFB3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,6716
Polymers59,6941
Non-polymers9765
Water34219
1
B: HUMAN PFKFB3
hetero molecules

B: HUMAN PFKFB3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,34112
Polymers119,3882
Non-polymers1,95310
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_555-y,-x,-z+1/61
Buried area8390 Å2
ΔGint-71.4 kcal/mol
Surface area37450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.630, 102.630, 258.210
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein HUMAN PFKFB3


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
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-8R2 / (2S)-2-amino-N-[4-[(2-amino-3-cyano-1H-indol-5-yl)oxy]phenyl]-3-hydroxy-propanamide


Mass: 351.359 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17N5O3
#4: Sugar ChemComp-FDP / 2,6-di-O-phosphono-beta-D-fructofuranose / FRUCTOSE-2,6-DIPHOSPHATE / 2,6-di-O-phosphono-beta-D-fructose / 2,6-di-O-phosphono-D-fructose / 2,6-di-O-phosphono-fructose


Type: D-saccharide, beta linking / Mass: 340.116 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C6H14O12P2
IdentifierTypeProgram
b-D-Fruf2PO36PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / 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: 4 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: 0.9763
DetectorType: DECTRIS PILATUS / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 3.01→88.88 Å / Num. obs: 14554 / % possible obs: 91.5 % / Observed criterion σ(I): 2 / Redundancy: 17.8 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 16.5
Reflection shellResolution: 2.89→3.01 Å / Redundancy: 7.6 % / Rmerge(I) obs: 0.62 / Mean I/σ(I) obs: 4.6 / % possible all: 94.2

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.01→88.88 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.936 / SU B: 24.675 / SU ML: 0.221 / Cross valid method: THROUGHOUT / ESU R: 1.486 / ESU R Free: 0.349 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22534 766 5 %RANDOM
Rwork0.18246 ---
obs0.18462 14554 91.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.973 Å2
Baniso -1Baniso -2Baniso -3
1-1.17 Å20.58 Å20 Å2
2--1.17 Å20 Å2
3----1.75 Å2
Refinement stepCycle: LAST / Resolution: 3.01→88.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3427 0 61 19 3507
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.023557
X-RAY DIFFRACTIONr_bond_other_d0.0020.022361
X-RAY DIFFRACTIONr_angle_refined_deg1.9321.9784838
X-RAY DIFFRACTIONr_angle_other_deg1.0423.0025738
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.715432
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.78923.642162
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.31915583
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.0611526
X-RAY DIFFRACTIONr_chiral_restr0.0860.2542
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213923
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02734
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.01→3.088 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.392 61 -
Rwork0.301 921 -
obs--92.73 %

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