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- PDB-5wbr: Structure of human Ketohexokinase complexed with hits from fragme... -

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Basic information

Entry
Database: PDB / ID: 5wbr
TitleStructure of human Ketohexokinase complexed with hits from fragment screening
ComponentsKetohexokinase
KeywordsTRANSFERASE / Ketohexokinase / Fragment-based drug discovery / SBDD
Function / homology
Function and homology information


Essential fructosuria / ketohexokinase / Fructose catabolism / ketohexokinase activity / regulation of glycogen metabolic process / response to sucrose / response to fructose / fructose metabolic process / response to zinc ion / response to glucose ...Essential fructosuria / ketohexokinase / Fructose catabolism / ketohexokinase activity / regulation of glycogen metabolic process / response to sucrose / response to fructose / fructose metabolic process / response to zinc ion / response to glucose / response to insulin / extracellular exosome / ATP binding / cytoplasm / cytosol
Similarity search - Function
Ketohexokinase / Carbohydrate kinase PfkB / pfkB family carbohydrate kinase / Ribokinase / Ribokinase-like / UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-A3Y / CITRIC ACID / Ketohexokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.58 Å
AuthorsPandit, J.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK).
Authors: Huard, K. / Ahn, K. / Amor, P. / Beebe, D.A. / Borzilleri, K.A. / Chrunyk, B.A. / Coffey, S.B. / Cong, Y. / Conn, E.L. / Culp, J.S. / Dowling, M.S. / Gorgoglione, M.F. / Gutierrez, J.A. / ...Authors: Huard, K. / Ahn, K. / Amor, P. / Beebe, D.A. / Borzilleri, K.A. / Chrunyk, B.A. / Coffey, S.B. / Cong, Y. / Conn, E.L. / Culp, J.S. / Dowling, M.S. / Gorgoglione, M.F. / Gutierrez, J.A. / Knafels, J.D. / Lachapelle, E.A. / Pandit, J. / Parris, K.D. / Perez, S. / Pfefferkorn, J.A. / Price, D.A. / Raymer, B. / Ross, T.T. / Shavnya, A. / Smith, A.C. / Subashi, T.A. / Tesz, G.J. / Thuma, B.A. / Tu, M. / Weaver, J.D. / Weng, Y. / Withka, J.M. / Xing, G. / Magee, T.V.
History
DepositionJun 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 13, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _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: Ketohexokinase
B: Ketohexokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,74511
Polymers68,1532
Non-polymers1,5919
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5200 Å2
ΔGint-94 kcal/mol
Surface area24320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.190, 86.160, 137.970
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Ketohexokinase / Hepatic fructokinase


Mass: 34076.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KHK / Production host: Escherichia coli (E. coli) / References: UniProt: P50053, ketohexokinase

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Non-polymers , 5 types, 46 molecules

#2: Chemical ChemComp-A3Y / 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-[(3S)-3-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile


Mass: 413.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H26F3N5O2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 3.62 Å3/Da / Density % sol: 65.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 17% PEG 8k, 0.1M Na-Citrate, 0.2M Ammonium sulfate, pH 4.5
Temp details: Room temperature

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 16, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.58→38.255 Å / Num. all: 31956 / Num. obs: 31956 / % possible obs: 99.8 % / Redundancy: 6.6 % / Biso Wilson estimate: 88.08 Å2 / Rpim(I) all: 0.045 / Rrim(I) all: 0.118 / Rsym value: 0.108 / Net I/av σ(I): 7 / Net I/σ(I): 17.4 / Num. measured all: 210546
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.58-2.726.72.50.33096546101.0352.7092.50.8100
2.72-2.886.11.5620.52659943460.6831.7091.5621.299.7
2.88-3.086.90.6921.12846641140.2810.7480.6922.9100
3.08-3.3370.3552.22669938310.1440.3840.3555.6100
3.33-3.656.80.19542385835190.080.2110.19510.1100
3.65-4.086.30.1057.32044132290.0450.1140.10518.699.9
4.08-4.716.40.04816.11810228230.020.0520.04835.399.5
4.71-5.776.80.038201669424550.0160.0410.03843.4100
5.77-8.156.10.02827.11174819140.0120.030.02852.899.5
8.15-38.2556.30.01251.8697411150.0050.0140.01298.898.5

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
SCALAdata scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3NBV

3nbv


Resolution: 2.58→38.26 Å / Cor.coef. Fo:Fc: 0.9447 / Cor.coef. Fo:Fc free: 0.9257 / SU R Cruickshank DPI: 0.324 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.315 / SU Rfree Blow DPI: 0.236 / SU Rfree Cruickshank DPI: 0.24
RfactorNum. reflection% reflectionSelection details
Rfree0.2415 1595 5.05 %RANDOM
Rwork0.2045 ---
obs0.2063 31568 98.91 %-
Displacement parametersBiso max: 153.96 Å2 / Biso mean: 76.64 Å2 / Biso min: 43.39 Å2
Baniso -1Baniso -2Baniso -3
1--0.5985 Å20 Å20 Å2
2--8.0019 Å20 Å2
3----7.4034 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.58→38.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4547 0 167 37 4751
Biso mean--96.35 66.36 -
Num. residues----597
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1679SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes120HARMONIC2
X-RAY DIFFRACTIONt_gen_planes719HARMONIC5
X-RAY DIFFRACTIONt_it4815HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion586SEMIHARMONIC5
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_contact5388SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4815HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6586HARMONIC21.2
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion20.86
LS refinement shellResolution: 2.58→2.67 Å / Rfactor Rfree error: 0 / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2388 148 5.43 %
Rwork0.2345 2580 -
all0.2348 2728 -
obs--98.91 %

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