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- PDB-9fhd: hKHK-C in fomplex with BI-9787 -

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Basic information

Entry
Database: PDB / ID: 9fhd
TitlehKHK-C in fomplex with BI-9787
ComponentsKetohexokinase
KeywordsSUGAR BINDING PROTEIN / Kinase / sugar kinase / Ketohexokinase / Fructokinase / co-structure
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
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.845 Å
AuthorsEbenhoch, R. / Pautsch, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2024
Title: Discovery of BI-9787, a potent zwitterionic ketohexokinase inhibitor with oral bioavailability.
Authors: Heine, N. / Weber, A. / Pautsch, A. / Gottschling, D. / Uphues, I. / Bauer, M. / Ebenhoch, R. / Magarkar, A. / Nosse, B. / Kley, J.T.
History
DepositionMay 27, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release

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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)69,4217
Polymers68,1532
Non-polymers1,2675
Water8,269459
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4020 Å2
ΔGint-68 kcal/mol
Surface area24660 Å2
Unit cell
Length a, b, c (Å)82.964, 86.345, 136.907
Angle α, β, γ (deg.)90, 90, 90
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-A1ICK / (2~{S})-3-[3-[[4-[bis(fluoranyl)methyl]-3-cyano-6-[(3~{S})-3-(dimethylamino)pyrrolidin-1-yl]pyridin-2-yl]amino]-4-methylsulfanyl-phenyl]-2-methyl-propanoic acid


Mass: 489.581 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29F2N5O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 459 / 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: 3.6 Å3/Da / Density % sol: 65.81 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion
Details: 13% PEG 8000, 0.2 M ammonium sulfate, 0.1 M tri-sodium citrate pH 4.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00002 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 18, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 1.84→73 Å / Num. obs: 73508 / % possible obs: 96.1 % / Redundancy: 12.7 % / CC1/2: 1 / Net I/σ(I): 16.1
Reflection shellResolution: 1.84→1.97 Å / Num. unique obs: 3675 / CC1/2: 0.7

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
Cootmodel building
Cootmodel building
autoPROCdata processing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.845→18.59 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.951 / SU R Cruickshank DPI: 0.142 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.12 / SU Rfree Blow DPI: 0.107 / SU Rfree Cruickshank DPI: 0.104
RfactorNum. reflection% reflectionSelection details
Rfree0.2045 2986 -RANDOM
Rwork0.1914 ---
obs0.192 73398 86.3 %-
Displacement parametersBiso mean: 44.35 Å2
Baniso -1Baniso -2Baniso -3
1--1.4561 Å20 Å20 Å2
2--0.5665 Å20 Å2
3---0.8897 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.845→18.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4579 0 83 459 5121
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0099352HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0116890HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2824SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1549HARMONIC5
X-RAY DIFFRACTIONt_it4749HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion589SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact7946SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.57
X-RAY DIFFRACTIONt_other_torsion14.41
LS refinement shellResolution: 1.845→1.92 Å
RfactorNum. reflection% reflection
Rfree0.3338 70 -
Rwork0.2783 --
obs--15.09 %
Refinement TLS params.

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)
10.3058-0.4836-0.2011.00821.03661.80950.1056-0.2336-0.4236-0.2336-0.04990.0275-0.42360.0275-0.05570.0778-0.01550.0702-0.06290.0050.03160.695211.6115.8819
20.60160.0199-0.15490.48520.16210.53050.0417-0.02730.0013-0.0273-0.05450.00180.00130.00180.0127-0.06730.02660.02050.03790.0440.0177-11.661319.378557.9842
30.8865-1.5482-2.76380.49053.36866.41340.0544-0.1351-0.1251-0.1351-0.1407-0.139-0.1251-0.1390.08620.0766-0.05620.13610.0785-0.05740.0507-15.768110.624236.5629
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|1-298 }A1 - 298
2X-RAY DIFFRACTION2{ B|-3-298 }B-3 - 298
3X-RAY DIFFRACTION3{ A|302 }A302
4X-RAY DIFFRACTION3{ B|303 }B303

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