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

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Basic information

Entry
Database: PDB / ID: 5ajz
TitleHuman PFKFB3 in complex with an indole inhibitor 5
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
6-O-phosphono-beta-D-fructofuranose / Chem-MJP / 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: 2.35 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)60,4385
Polymers59,6941
Non-polymers7434
Water4,972276
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)120,87510
Polymers119,3882
Non-polymers1,4878
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_554x,x-y,-z-1/61
Buried area5760 Å2
ΔGint-42.3 kcal/mol
Surface area38200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.480, 102.480, 258.960
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-2109-

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 / 6PF-2-K/FRU-2 / 6-P2ASE BRAIN/PLACENTA-TYPE ISOZYME / ...6PF-2-K/FRU-2 / 6-P2ASE 3 / PFK/FBPASE 3 / 6PF-2-K/FRU-2 / 6-P2ASE BRAIN/PLACENTA-TYPE ISOZYME / RENAL CARCINOMA ANTIGEN NY-REN-56 / IPFK-2 / 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
#3: 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, 279 molecules

#2: Chemical ChemComp-PHS / PHOSPHONIC ACID


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


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-MJP / 2-azanyl-N-[4-[(3-cyano-1H-indol-5-yl)oxy]phenyl]ethanamide


Mass: 306.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14N4O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 276 / 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: 3.29 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: 0.976251
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976251 Å / Relative weight: 1
ReflectionResolution: 2.35→88.75 Å / Num. obs: 34476 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 6.5 % / Biso Wilson estimate: 54.84 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 14.8
Reflection shellResolution: 2.35→2.36 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 2.9 / % 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: 2.35→88.75 Å / Cor.coef. Fo:Fc: 0.9395 / Cor.coef. Fo:Fc free: 0.9148 / SU R Cruickshank DPI: 0.193 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.209 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.173
RfactorNum. reflection% reflectionSelection details
Rfree0.2204 1733 5.04 %RANDOM
Rwork0.1829 ---
obs0.1848 34367 99.78 %-
Displacement parametersBiso mean: 52.43 Å2
Baniso -1Baniso -2Baniso -3
1--1.8956 Å20 Å20 Å2
2---1.8956 Å20 Å2
3---3.7912 Å2
Refine analyzeLuzzati coordinate error obs: 0.285 Å
Refinement stepCycle: LAST / Resolution: 2.35→88.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3511 0 48 276 3835
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0093639HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.034939HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1274SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes88HARMONIC2
X-RAY DIFFRACTIONt_gen_planes548HARMONIC5
X-RAY DIFFRACTIONt_it3639HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion17.87
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion469SEMIHARMONIC5
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_contact4382SEMIHARMONIC4
LS refinement shellResolution: 2.35→2.42 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2622 139 4.75 %
Rwork0.1981 2789 -
all0.2014 2928 -
obs--99.78 %
Refinement TLS params.Method: refined / Origin x: -30.6605 Å / Origin y: -28.0518 Å / Origin z: -9.0957 Å
111213212223313233
T-0.0219 Å20.0036 Å20.0132 Å2--0.1498 Å20.0173 Å2---0.1336 Å2
L0.6161 °20.1023 °2-0.0741 °2-0.7436 °2-0.1929 °2--0.8814 °2
S0.0286 Å °-0.0346 Å °-0.0467 Å °0.2245 Å °-0.0762 Å °0.0401 Å °0.1524 Å °0.0027 Å °0.0475 Å °
Refinement TLS groupSelection details: CHAIN A

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