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- PDB-6zh0: Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-... -

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Basic information

Entry
Database: PDB / ID: 6zh0
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 / 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 / N-(3-chlorophenyl)-2,2,2-trifluoroacetamide / Galactokinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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
Citation
Journal: 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.
#1: Journal: Science / Year: 2020
Title: In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.
Authors: Beata Turoňová / Mateusz Sikora / Christoph Schürmann / Wim J H Hagen / Sonja Welsch / Florian E C Blanc / Sören von Bülow / Michael Gecht / Katrin Bagola / Cindy Hörner / Ger van ...Authors: Beata Turoňová / Mateusz Sikora / Christoph Schürmann / Wim J H Hagen / Sonja Welsch / Florian E C Blanc / Sören von Bülow / Michael Gecht / Katrin Bagola / Cindy Hörner / Ger van Zandbergen / Jonathan Landry / Nayara Trevisan Doimo de Azevedo / Shyamal Mosalaganti / Andre Schwarz / Roberto Covino / Michael D Mühlebach / Gerhard Hummer / Jacomine Krijnse Locker / Martin Beck /
Abstract: The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the primary focus for vaccine development. In this study, we combined cryo- ...The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the primary focus for vaccine development. In this study, we combined cryo-electron tomography, subtomogram averaging, and molecular dynamics simulations to structurally analyze S in situ. Compared with the recombinant S, the viral S was more heavily glycosylated and occurred mostly in the closed prefusion conformation. We show that the stalk domain of S contains three hinges, giving the head unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and potentially to the development of safe vaccines.
History
DepositionJun 20, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 13, 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)174,89814
Polymers172,4124
Non-polymers2,48610
Water4,161231
1
A: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8574
Polymers43,1031
Non-polymers7543
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8574
Polymers43,1031
Non-polymers7543
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8574
Polymers43,1031
Non-polymers7543
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Galactokinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,3272
Polymers43,1031
Non-polymers2241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.529, 115.004, 120.849
Angle α, β, γ (deg.)90.000, 100.650, 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-WNP / N-(3-chlorophenyl)-2,2,2-trifluoroacetamide


Mass: 223.580 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H5ClF3NO / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 2.91 Å3/Da / Density % sol: 57.77 %
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: 2.27→118.77 Å / Num. obs: 90924 / % possible obs: 99.8 % / Redundancy: 3.5 % / CC1/2: 0.996 / Rmerge(I) obs: 0.13 / Rpim(I) all: 0.082 / Rrim(I) all: 0.154 / Net I/σ(I): 4.7 / Num. measured all: 316693
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
2.27-2.393.61.92847546132740.4521.1862.2670.599.8
7.18-118.773.40.025995829420.9990.0160.0318.899.5

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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: 2.5→118.77 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.894 / SU B: 33.169 / SU ML: 0.327 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.458 / ESU R Free: 0.307 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2897 3354 4.9 %RANDOM
Rwork0.2389 ---
obs0.2414 64856 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 146.24 Å2 / Biso mean: 50.803 Å2 / Biso min: 32.62 Å2
Baniso -1Baniso -2Baniso -3
1--0.89 Å2-0 Å20.67 Å2
2---1.79 Å20 Å2
3---2.27 Å2
Refinement stepCycle: final / Resolution: 2.5→118.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10854 0 169 231 11254
Biso mean--62.81 55.77 -
Num. residues----1542
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.01311236
X-RAY DIFFRACTIONr_bond_other_d0.0090.01710121
X-RAY DIFFRACTIONr_angle_refined_deg1.921.65315362
X-RAY DIFFRACTIONr_angle_other_deg1.3721.57723225
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.32551534
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.8320.994463
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.368151504
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1491575
X-RAY DIFFRACTIONr_chiral_restr0.070.21525
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213031
X-RAY DIFFRACTIONr_gen_planes_other0.0040.022307
LS refinement shellResolution: 2.5→2.565 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 225 -
Rwork0.322 4812 -
all-5037 -
obs--99.86 %
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)
13.1083-1.31840.01312.10330.51312.39410.32720.4183-0.5302-0.1447-0.25140.10370.08760.1957-0.07580.52470.1037-0.20230.8343-0.05030.145414.666-14.9076-37.2266
20.9701-0.44620.49481.1464-0.71353.069-0.0429-0.2127-0.0880.18090.10380.2406-0.1571-0.2512-0.06090.47590.062-0.09460.68170.00050.0921-10.99355.8991-44.9371
31.20580.1766-0.27060.7691-0.23713.08640.0156-0.0126-0.0872-0.04790.02590.08310.24670.0297-0.04150.33810.0079-0.11750.55630.01260.0556-30.3429-9.961-98.4511
43.5906-0.63670.40.89280.73832.70280.03510.5921-0.2746-0.0418-0.0714-0.07880.39480.15730.03640.45410.0091-0.08050.7297-0.01430.11313.5596-4.7939-95.2688
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 501
2X-RAY DIFFRACTION2B3 - 501
3X-RAY DIFFRACTION3E2 - 401
4X-RAY DIFFRACTION4D7 - 392

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