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

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Basic information

Entry
Database: PDB / ID: 6zgz
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-SSY / 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

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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)174,23511
Polymers172,4124
Non-polymers1,8237
Water10,377576
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
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,3342
Polymers43,1031
Non-polymers2311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.210, 114.299, 120.807
Angle α, β, γ (deg.)90.000, 100.540, 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 / 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-SSY / ~{N}-(3-ethanoylphenyl)-2,2,2-tris(fluoranyl)ethanamide


Mass: 231.171 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H8F3NO2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 576 / 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: 2.88 Å3/Da / Density % sol: 57.32 %
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: 2.07→114.3 Å / Num. obs: 118894 / % possible obs: 100 % / Redundancy: 3.4 % / CC1/2: 0.99 / Rmerge(I) obs: 0.144 / Rpim(I) all: 0.092 / Rrim(I) all: 0.171 / Net I/σ(I): 5.9 / Num. measured all: 400803 / Scaling rejects: 271
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
2.07-2.123.21.3292825887850.490.8811.6199.9
9.26-114.33.70.03508513880.9850.0190.03525.899.8

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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→82.49 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.913 / SU B: 17.539 / SU ML: 0.208 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.284 / ESU R Free: 0.225 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2563 4253 4.9 %RANDOM
Rwork0.2142 ---
obs0.2163 82481 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 151.98 Å2 / Biso mean: 43.168 Å2 / Biso min: 18.32 Å2
Baniso -1Baniso -2Baniso -3
1--2.32 Å20 Å2-0.17 Å2
2--3.66 Å20 Å2
3----1.19 Å2
Refinement stepCycle: final / Resolution: 2.3→82.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10871 0 130 576 11577
Biso mean--45.33 44.06 -
Num. residues----1534
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.01311239
X-RAY DIFFRACTIONr_bond_other_d0.0050.01710184
X-RAY DIFFRACTIONr_angle_refined_deg1.8571.65415361
X-RAY DIFFRACTIONr_angle_other_deg1.4151.57723413
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.18751532
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.30521.309466
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.857151543
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9261571
X-RAY DIFFRACTIONr_chiral_restr0.0780.21524
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213041
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022286
LS refinement shellResolution: 2.3→2.36 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.317 294 -
Rwork0.288 6069 -
all-6363 -
obs--99.5 %
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)
13.1109-1.97150.39682.24640.01723.11670.52130.6177-0.5459-0.2275-0.41330.23390.17140.3686-0.1080.45560.1603-0.20550.1932-0.11760.138114.7475-14.8144-37.1392
21.1854-0.61150.92881.3285-0.84844.0824-0.0706-0.2493-0.1040.17180.16160.2552-0.0707-0.2825-0.09110.36680.0726-0.06390.1060.00650.0789-11.19345.9533-44.8118
31.44210.2241-0.19030.7347-0.42214.09860.0673-0.0145-0.0769-0.07390.02080.12550.23260.095-0.08810.2683-0.0067-0.11140.00420.00790.0643-30.2059-9.9027-98.4267
44.5464-0.82440.40371.20590.84542.45750.01060.8985-0.231-0.0323-0.1057-0.0260.34920.21480.09510.35560.0032-0.06070.2699-0.01990.0763.3613-4.735-94.6027
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 401
2X-RAY DIFFRACTION2B2 - 601
3X-RAY DIFFRACTION3E3 - 401
4X-RAY DIFFRACTION4D7 - 401

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