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- PDB-6zgx: Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-... -

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Basic information

Entry
Database: PDB / ID: 6zgx
TitleStructure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide
ComponentsGalactokinase
KeywordsTRANSFERASE / GALK1 / galactokinase 1 / fragment screening / allosteric fragment / binding hotspt
Function / homology
Function and homology information


glycolytic process from galactose / Defective GALK1 causes GALCT2 / galactitol metabolic process / galactokinase / galactokinase activity / galactose catabolic process / Galactose catabolism / galactose catabolic process via UDP-galactose / galactose binding / galactose metabolic process ...glycolytic process from galactose / Defective GALK1 causes GALCT2 / galactitol metabolic process / galactokinase / galactokinase activity / galactose catabolic process / Galactose catabolism / galactose catabolic process via UDP-galactose / galactose binding / galactose metabolic process / extracellular exosome / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
Galactokinase, N-terminal domain / Galactokinase, conserved site / Galactokinase galactose-binding signature / Galactokinase signature. / Galactokinase / Mevalonate/galactokinase / GHMP kinase, ATP-binding, conserved site / GHMP kinases putative ATP-binding domain. / GHMP kinase, C-terminal domain / GHMP kinases C terminal ...Galactokinase, N-terminal domain / Galactokinase, conserved site / Galactokinase galactose-binding signature / Galactokinase signature. / Galactokinase / Mevalonate/galactokinase / GHMP kinase, ATP-binding, conserved site / GHMP kinases putative ATP-binding domain. / GHMP kinase, C-terminal domain / GHMP kinases C terminal / GHMP kinase N-terminal domain / GHMP kinases N terminal domain / GHMP kinase, C-terminal domain superfamily / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
beta-D-galactopyranose / Chem-HFK / Chem-S6V / Galactokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.86 Å
AuthorsMackinnon, S.R. / Bezerra, G.A. / Zhang, M. / Foster, W. / Krojer, T. / Brandao-Neto, J. / Douangamath, A. / Arrowsmith, C. / Edwards, A. / Bountra, C. ...Mackinnon, S.R. / Bezerra, G.A. / Zhang, M. / Foster, W. / Krojer, T. / Brandao-Neto, J. / Douangamath, A. / Arrowsmith, C. / Edwards, A. / Bountra, C. / Brennan, P. / Lai, K. / Yue, W.W.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust092809/Z/10/Z United Kingdom
CitationJournal: Acs Chem.Biol. / Year: 2021
Title: Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia.
Authors: Mackinnon, S.R. / Krojer, T. / Foster, W.R. / Diaz-Saez, L. / Tang, M. / Huber, K.V.M. / von Delft, F. / Lai, K. / Brennan, P.E. / Arruda Bezerra, G. / Yue, W.W.
History
DepositionJun 20, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 29, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 28, 2021Group: 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
Revision 1.3Jan 24, 2024Group: 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

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Assembly

Deposited unit
A: Galactokinase
B: Galactokinase
D: Galactokinase
E: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)174,25111
Polymers172,4124
Non-polymers1,8397
Water8,215456
1
A: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,6343
Polymers43,1031
Non-polymers5312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,6343
Polymers43,1031
Non-polymers5312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
D: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,3502
Polymers43,1031
Non-polymers2471
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
E: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,6343
Polymers43,1031
Non-polymers5312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.772, 114.447, 120.924
Angle α, β, γ (deg.)90.000, 100.550, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Galactokinase / / Galactose kinase


Mass: 43102.977 Da / Num. of mol.: 4 / Mutation: K252A, E253A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GALK1, GALK / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P51570, galactokinase
#2: Sugar ChemComp-GAL / beta-D-galactopyranose / beta-D-galactose / D-galactose / galactose / Galactose


Type: D-saccharide, beta linking / Mass: 180.156 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C6H12O6
IdentifierTypeProgram
DGalpbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
b-D-galactopyranoseCOMMON NAMEGMML 1.0
b-D-GalpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GalSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-HFK / 2-(1,3-benzoxazol-2-ylamino)spiro[1,6,7,8-tetrahydroquinazoline-4,1'-cyclohexane]-5-one


Mass: 350.414 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C20H22N4O2
#4: Chemical ChemComp-S6V / 1-[2-(2-oxidanylidenepyrrolidin-1-yl)ethyl]-3-phenyl-urea


Mass: 247.293 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H17N3O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 456 / 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: 2.97 Å3/Da / Density % sol: 58.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M MOPS/sodium HEPES pH 7.0-7.5, 40-50 % Morpheus Precipitant Mix 4 (50% mix = 12.5% MPD, 12.5% PEG1000, 12.5% PEG3350), 0.1 M Morpheus Carboxylic acids mix (0.02M each of - sodium ...Details: 0.1 M MOPS/sodium HEPES pH 7.0-7.5, 40-50 % Morpheus Precipitant Mix 4 (50% mix = 12.5% MPD, 12.5% PEG1000, 12.5% PEG3350), 0.1 M Morpheus Carboxylic acids mix (0.02M each of - sodium formate, ammonium acetate, sodium citrate tribasic dehydrate, sodium potassium tartrate tetrahydrate and sodium oxamate)
PH range: 7.0-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.86→114.44 Å / Num. obs: 164750 / % possible obs: 99.6 % / Redundancy: 3.4 % / CC1/2: 0.988 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.052 / Rrim(I) all: 0.096 / Net I/σ(I): 7 / Num. measured all: 560340 / Scaling rejects: 264
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.5 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.86-1.910.83642310120620.7060.520.9861.199.1
8.32-114.440.037673619130.980.0230.04420.499.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSdata reduction
Aimless0.7.2data scaling
PDB_EXTRACT3.25data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1WUU
Resolution: 1.86→82.59 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.929 / SU B: 5.844 / SU ML: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.153 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2742 8248 5 %RANDOM
Rwork0.2491 ---
obs0.2503 156381 99.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120.86 Å2 / Biso mean: 38.869 Å2 / Biso min: 15.22 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å2-0 Å2-1.73 Å2
2--3.23 Å2-0 Å2
3----2.33 Å2
Refinement stepCycle: final / Resolution: 1.86→82.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10954 0 132 456 11542
Biso mean--35.39 40.97 -
Num. residues----1532
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01211307
X-RAY DIFFRACTIONr_angle_refined_deg1.4121.64915434
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.06551524
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.07420.704483
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.57151591
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0451582
X-RAY DIFFRACTIONr_chiral_restr0.1080.21520
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.028724
LS refinement shellResolution: 1.86→1.907 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.363 603 -
Rwork0.374 11230 -
obs--97.02 %

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