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

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Basic information

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


Essential fructosuria / ketohexokinase / ketohexokinase activity / Fructose catabolism / regulation of glycogen metabolic process / response to sucrose / response to fructose / fructose metabolic process / response to zinc ion / response to glucose ...Essential fructosuria / ketohexokinase / ketohexokinase activity / Fructose catabolism / 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 / cytosol / cytoplasm
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
3-(trifluoromethyl)quinoxalin-2(1H)-one / Ketohexokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.74 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)68,9409
Polymers68,1532
Non-polymers7877
Water45025
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4690 Å2
ΔGint-98 kcal/mol
Surface area24620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.910, 85.020, 138.780
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Ketohexokinase / Hepatic fructokinase / 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
#2: Chemical ChemComp-A2J / 3-(trifluoromethyl)quinoxalin-2(1H)-one


Mass: 214.144 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H5F3N2O
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 3.59 Å3/Da / Density % sol: 65.72 %
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: Oct 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.74→138.78 Å / Num. obs: 26032 / % possible obs: 98.6 % / Redundancy: 6.1 % / Biso Wilson estimate: 95.74 Å2 / Rpim(I) all: 0.018 / Rrim(I) all: 0.046 / Rsym value: 0.038 / Net I/av σ(I): 14.2 / Net I/σ(I): 25.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value% possible all
2.74-2.894.10.4141.90.2530.5410.41490.5
2.89-3.076.30.2732.80.1280.3270.273100
3.07-3.286.80.15450.0690.1810.154100
3.28-3.546.50.0799.60.0370.0940.079100
3.54-3.886.60.04914.70.0230.0590.049100
3.88-4.346.70.03619.70.0160.0420.036100
4.34-5.016.20.02923.10.0140.0340.029100
5.01-6.136.20.02823.40.0130.0330.028100
6.13-8.686.10.02326.50.0110.0270.023100
8.68-138.785.50.021280.010.0240.02199.7

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3NBV

3nbv


Resolution: 2.74→71.17 Å / Cor.coef. Fo:Fc: 0.9463 / Cor.coef. Fo:Fc free: 0.9313 / SU R Cruickshank DPI: 0.398 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.391 / SU Rfree Blow DPI: 0.26 / SU Rfree Cruickshank DPI: 0.265
RfactorNum. reflection% reflectionSelection details
Rfree0.2285 1322 5.09 %RANDOM
Rwork0.1837 ---
obs0.186 25976 98.24 %-
Displacement parametersBiso max: 174.09 Å2 / Biso mean: 89.38 Å2 / Biso min: 41.46 Å2
Baniso -1Baniso -2Baniso -3
1-18.1095 Å20 Å20 Å2
2---6.8529 Å20 Å2
3----11.2566 Å2
Refine analyzeLuzzati coordinate error obs: 0.379 Å
Refinement stepCycle: final / Resolution: 2.74→71.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4547 0 59 25 4631
Biso mean--123.18 74.6 -
Num. residues----597
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1625SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes120HARMONIC2
X-RAY DIFFRACTIONt_gen_planes708HARMONIC5
X-RAY DIFFRACTIONt_it4693HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion583SEMIHARMONIC5
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_contact5097SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4693HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6363HARMONIC21.17
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion20.89
LS refinement shellResolution: 2.74→2.85 Å / Rfactor Rfree error: 0 / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.3222 134 5.44 %
Rwork0.2489 2331 -
all0.2529 2465 -
obs--98.24 %

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