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

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Basic information

Entry
Database: PDB / ID: 5wbz
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 / ketohexokinase activity / fructose binding / Fructose catabolism / regulation of glycogen metabolic process / response to sucrose / response to fructose / fructose metabolic process / response to zinc ion ...Essential fructosuria / ketohexokinase / ketohexokinase activity / fructose binding / 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 / protein homodimerization activity / extracellular exosome / ATP binding / identical protein 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
Chem-A4J / CITRIC ACID / Ketohexokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 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)69,5709
Polymers68,1532
Non-polymers1,4177
Water3,171176
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4520 Å2
ΔGint-65 kcal/mol
Surface area24750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.180, 86.380, 137.620
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


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-A4J / 6-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-2-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile


Mass: 372.342 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H19F3N4O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H8O7
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 3.63 Å3/Da / Density % sol: 66.09 %
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: 2.4→137.616 Å / Num. all: 39513 / Num. obs: 39513 / % possible obs: 99.6 % / Redundancy: 6 % / Biso Wilson estimate: 63.61 Å2 / Rpim(I) all: 0.034 / Rrim(I) all: 0.086 / Rsym value: 0.074 / Net I/av σ(I): 7.4 / Net I/σ(I): 14.3 / Num. measured all: 236415
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
2.4-2.534.20.37522322255360.220.4680.3752.797.7
2.53-2.686.30.3132.33423954260.1440.3660.3134.8100
2.68-2.866.40.2213.33275150950.1010.2570.2217.299.9
2.86-3.096.50.1415.13095247550.0640.1630.14111.4100
3.09-3.396.60.172872943650.0450.1150.116.4100
3.39-3.796.10.07592424640050.0350.0880.07521.399.9
3.79-4.386.20.06510.12179635430.030.0750.06525.399.9
4.38-5.3660.05711.41807630200.0260.0660.05727.199.9
5.36-7.586.10.05511.71451323780.0250.0630.05527.499.8
7.58-137.6165.70.0415.3789113900.0180.0460.0428.699.5

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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: 2.4→73.16 Å / Cor.coef. Fo:Fc: 0.9478 / Cor.coef. Fo:Fc free: 0.933 / SU R Cruickshank DPI: 0.223 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.224 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.179
RfactorNum. reflection% reflectionSelection details
Rfree0.2136 1976 5.03 %RANDOM
Rwork0.1887 ---
obs0.1899 39317 99.63 %-
Displacement parametersBiso max: 145.23 Å2 / Biso mean: 56.13 Å2 / Biso min: 25.33 Å2
Baniso -1Baniso -2Baniso -3
1-1.1537 Å20 Å20 Å2
2---1.0203 Å20 Å2
3----0.1335 Å2
Refine analyzeLuzzati coordinate error obs: 0.287 Å
Refinement stepCycle: final / Resolution: 2.4→73.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4547 0 141 176 4864
Biso mean--69.29 54.01 -
Num. residues----597
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1667SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes120HARMONIC2
X-RAY DIFFRACTIONt_gen_planes721HARMONIC5
X-RAY DIFFRACTIONt_it4779HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion589SEMIHARMONIC5
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_contact5341SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4779HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6524HARMONIC21.15
X-RAY DIFFRACTIONt_omega_torsion3.32
X-RAY DIFFRACTIONt_other_torsion18.28
LS refinement shellResolution: 2.4→2.46 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2093 141 5.13 %
Rwork0.2293 2609 -
all0.2283 2750 -
obs--99.63 %

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