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

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Basic information

Entry
Database: PDB / ID: 6zgy
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 catabolism / galactose catabolic process via UDP-galactose, Leloir pathway / galactose binding / galactose metabolic process / extracellular exosome ...glycolytic process from galactose / Defective GALK1 causes GALCT2 / galactitol metabolic process / galactokinase / galactokinase activity / Galactose catabolism / galactose catabolic process via UDP-galactose, Leloir pathway / galactose binding / galactose metabolic process / extracellular exosome / ATP binding / membrane / cytoplasm / cytosol
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 / (2,5-dimethylphenyl) pyridine-4-carboxylate / Galactokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)174,45812
Polymers172,4124
Non-polymers2,0468
Water8,035446
1
A: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8614
Polymers43,1031
Non-polymers7583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8614
Polymers43,1031
Non-polymers7583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
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
4
D: Galactokinase


Theoretical massNumber of molelcules
Total (without water)43,1031
Polymers43,1031
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.308, 114.628, 120.824
Angle α, β, γ (deg.)90.000, 100.600, 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
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


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-QL5 / (2,5-dimethylphenyl) pyridine-4-carboxylate


Mass: 227.259 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H13NO2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 446 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.89 Å3/Da / Density % sol: 57.5 %
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 formate, ...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: 1.92→118.76 Å / Num. obs: 147920 / % possible obs: 99.7 % / Redundancy: 3.5 % / CC1/2: 0.996 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.069 / Rrim(I) all: 0.13 / Net I/σ(I): 5.8 / Num. measured all: 510767 / Scaling rejects: 16
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.92-2.033.32.71971882215290.3611.7513.2430.399.5
6.09-118.763.40.0461606547800.9960.0290.05522.399.2

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.2data scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1WUU

1wuu


Resolution: 2.3→118.76 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.925 / SU B: 17.243 / SU ML: 0.198 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.275 / ESU R Free: 0.223 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2537 4336 5 %RANDOM
Rwork0.2059 ---
obs0.2083 82504 99.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 158.87 Å2 / Biso mean: 49.213 Å2 / Biso min: 24.13 Å2
Baniso -1Baniso -2Baniso -3
1--0.85 Å2-0 Å2-2.48 Å2
2--3.38 Å20 Å2
3----1.5 Å2
Refinement stepCycle: final / Resolution: 2.3→118.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11031 0 148 446 11625
Biso mean--50.66 50.76 -
Num. residues----1542
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01311414
X-RAY DIFFRACTIONr_bond_other_d0.0040.01710448
X-RAY DIFFRACTIONr_angle_refined_deg1.881.65315582
X-RAY DIFFRACTIONr_angle_other_deg1.4161.57624010
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.0551540
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.94920.788495
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.273151610
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7151584
X-RAY DIFFRACTIONr_chiral_restr0.0870.21530
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213168
X-RAY DIFFRACTIONr_gen_planes_other0.0030.022363
LS refinement shellResolution: 2.3→2.36 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 303 -
Rwork0.276 6096 -
all-6399 -
obs--99.83 %
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)
12.9286-1.52210.56492.16110.16093.15470.46140.4913-0.5591-0.2399-0.28260.15030.16330.3888-0.17890.34440.1365-0.09940.1776-0.09620.121715.0989-15.1015-37.7657
21.4138-0.56290.81751.5101-0.843.9861-0.0879-0.2512-0.07850.15210.14670.2216-0.1439-0.2825-0.05880.29140.07620.04040.11330.01140.0373-10.816.1545-44.7775
31.29610.13690.09350.9237-0.34683.8310.09160.0211-0.0881-0.0780.03170.14920.21480.0539-0.12330.1553-0.0186-0.02260.03350.00730.0352-30.2969-10.0044-98.2266
43.7732-0.56620.63341.10820.67292.5057-0.01140.7524-0.1324-0.0554-0.0643-0.05470.39510.2670.07570.27880.00180.06020.2659-0.00050.033.3835-4.9859-94.6428
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 401
2X-RAY DIFFRACTION2B2 - 401
3X-RAY DIFFRACTION3E2 - 401
4X-RAY DIFFRACTION4D8 - 392

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