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- PDB-8ug1: Crystal structure of KHK-C and compound 13 -

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Basic information

Entry
Database: PDB / ID: 8ug1
TitleCrystal structure of KHK-C and compound 13
ComponentsKetohexokinase
KeywordsSUGAR BINDING PROTEIN / Inhibitor
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-like
Similarity search - Domain/homology
Chem-WNH / Ketohexokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsDurbin, J.D. / Guo, S.Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.
Authors: Durham, T.B. / Hao, J. / Spinazze, P. / Stack, D.R. / Toth, J.L. / Massey, S. / Mbofana, C.T. / Johnston, R.D. / Lineswala, J.P. / Wrobleski, A. / Minguez, J.M. / Perez, C. / Smith, D.L. / ...Authors: Durham, T.B. / Hao, J. / Spinazze, P. / Stack, D.R. / Toth, J.L. / Massey, S. / Mbofana, C.T. / Johnston, R.D. / Lineswala, J.P. / Wrobleski, A. / Minguez, J.M. / Perez, C. / Smith, D.L. / Lamar, J. / Leon, R. / Corkins, C. / Durbin, J. / Tung, F. / Guo, S. / Linder, R.J. / Yumibe, N. / Wang, W. / MacKrell, J. / Antonellis, M. / Mascaro, B.
History
DepositionOct 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)70,36315
Polymers68,5542
Non-polymers1,81013
Water5,801322
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5510 Å2
ΔGint-120 kcal/mol
Surface area24170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.583, 86.793, 136.432
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Ketohexokinase


Mass: 34276.820 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
#2: Chemical ChemComp-WNH / {(2R)-1-[(4M)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-2-yl}methanol


Mass: 382.383 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21F3N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 322 / 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: 3.57 Å3/Da / Density % sol: 65.51 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: Polyethylene glycol 8,000, Ammonium Sulfate, tri-Sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.99→59.9 Å / Num. obs: 68419 / % possible obs: 100 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.045 / Net I/σ(I): 18.2
Reflection shellResolution: 1.99→2.09 Å / Rmerge(I) obs: 0.581 / Num. unique obs: 9857

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
SCALAdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.99→59.9 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.96 / SU B: 3.146 / SU ML: 0.086 / Cross valid method: THROUGHOUT / ESU R: 0.117 / ESU R Free: 0.115 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.20477 3344 4.9 %RANDOM
Rwork0.17252 ---
obs0.17412 64548 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 54.787 Å2
Baniso -1Baniso -2Baniso -3
1--0.59 Å2-0 Å20 Å2
2--1.14 Å2-0 Å2
3----0.55 Å2
Refinement stepCycle: 1 / Resolution: 1.99→59.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4523 0 112 322 4957
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0124764
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8961.6276477
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4765611
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.65321.844244
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.7615736
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.1621536
X-RAY DIFFRACTIONr_chiral_restr0.1340.2595
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.023746
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it5.2545.2792435
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it6.3837.873049
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it7.1245.7482329
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined9.73173.0747118
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.99→2.042 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 234 -
Rwork0.25 4740 -
obs--100 %

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