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- PDB-6w0x: Structure of KHK in complex with compound 4 (6-[(1~{S},5~{R})-6-(... -

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Basic information

Entry
Database: PDB / ID: 6w0x
TitleStructure of KHK in complex with compound 4 (6-[(1~{S},5~{R})-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile)
ComponentsKetohexokinase
KeywordsTRANSFERASE / Ketohexokinase
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-like
Similarity search - Domain/homology
Chem-S6J / Ketohexokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsJasti, J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.
Authors: Futatsugi, K. / Smith, A.C. / Tu, M. / Raymer, B. / Ahn, K. / Coffey, S.B. / Dowling, M.S. / Fernando, D.P. / Gutierrez, J.A. / Huard, K. / Jasti, J. / Kalgutkar, A.S. / Knafels, J.D. / ...Authors: Futatsugi, K. / Smith, A.C. / Tu, M. / Raymer, B. / Ahn, K. / Coffey, S.B. / Dowling, M.S. / Fernando, D.P. / Gutierrez, J.A. / Huard, K. / Jasti, J. / Kalgutkar, A.S. / Knafels, J.D. / Pandit, J. / Parris, K.D. / Perez, S. / Pfefferkorn, J.A. / Price, D.A. / Ryder, T. / Shavnya, A. / Stock, I.A. / Tsai, A.S. / Tesz, G.J. / Thuma, B.A. / Weng, Y. / Wisniewska, H.M. / Xing, G. / Zhou, J. / Magee, T.V.
History
DepositionMar 3, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2020Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 9, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.3Oct 11, 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)69,0826
Polymers68,1532
Non-polymers9294
Water5,278293
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3730 Å2
ΔGint-49 kcal/mol
Surface area24450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.790, 85.820, 137.760
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-S6J / 6-[(1~{S},5~{R})-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl]-2-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile


Mass: 368.354 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H19F3N4O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 293 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 65.74 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 17-20% PEG8000, 100 mM sodium citrate, pH 4.4-4.7, 0.2 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 25, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→70.96 Å / Num. obs: 58088 / % possible obs: 93.6 % / Redundancy: 6.5 % / CC1/2: 0.999 / Net I/σ(I): 19.7
Reflection shellResolution: 2.38→2.39 Å / Num. unique obs: 400 / CC1/2: 0.791

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5WBM

5wbm


Resolution: 2.38→20.94 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.952 / SU R Cruickshank DPI: 0.193 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.2 / SU Rfree Blow DPI: 0.16 / SU Rfree Cruickshank DPI: 0.159
RfactorNum. reflection% reflectionSelection details
Rfree0.206 2200 5.04 %RANDOM
Rwork0.186 ---
obs0.187 43610 75.2 %-
Displacement parametersBiso max: 164.22 Å2 / Biso mean: 71.74 Å2 / Biso min: 34.58 Å2
Baniso -1Baniso -2Baniso -3
1--3.9587 Å20 Å20 Å2
2--1.9325 Å20 Å2
3---2.0262 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.38→20.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4547 0 62 293 4902
Biso mean--69.14 69.98 -
Num. residues----597
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1648SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes831HARMONIC5
X-RAY DIFFRACTIONt_it4698HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion590SEMIHARMONIC5
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_contact5319SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4698HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6371HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion18.35
LS refinement shellResolution: 2.38→2.48 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2462 40 4.58 %
Rwork0.2242 833 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.171-0.7834-0.24811.59921.18633.31270.20260.21680.4504-0.3241-0.13850.2413-1.038-0.04-0.064-0.026-0.03340.125-0.32660.0012-0.11-0.763812.228116.3272
21.83050.0708-0.1691.2928-0.03971.56320.0158-0.2134-0.3514-0.0804-0.0851-0.02880.18460.01740.0692-0.27770.05820.042-0.15950.0693-0.1571-11.874718.651458.2154
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A3 - 298
2X-RAY DIFFRACTION2{ B|* }B-2 - 298

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