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- PDB-4qga: S.aureus TMK in complex with potent inhibitor compound 19, 2-(3-C... -

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Basic information

Entry
Database: PDB / ID: 4qga
TitleS.aureus TMK in complex with potent inhibitor compound 19, 2-(3-CHLOROPHENOXY)-3-FLUORO-4-{[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]METHYL}BENZOIC ACID
ComponentsThymidylate kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE/TRANSFERASE INHIBITOR kinase / thymidine monphosphate / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


dTMP kinase / thymidylate kinase activity / dTDP biosynthetic process / dTTP biosynthetic process / phosphorylation / ATP binding
Similarity search - Function
Thymidylate kinase, conserved site / Thymidylate kinase signature. / Thymidylate kinase / Thymidylate kinase-like domain / Thymidylate kinase / P-loop containing nucleotide triphosphate hydrolases / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-31Z / Thymidylate kinase
Similarity search - Component
Biological speciesStaphylococcus aureus subsp. aureus (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.94 Å
AuthorsOlivier, N.B.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Antibacterial inhibitors of gram-positive thymidylate kinase: structure-activity relationships and chiral preference of a new hydrophobic binding region.
Authors: Kawatkar, S.P. / Keating, T.A. / Olivier, N.B. / Breen, J.N. / Green, O.M. / Guler, S.Y. / Hentemann, M.F. / Loch, J.T. / McKenzie, A.R. / Newman, J.V. / Otterson, L.G. / Martinez-Botella, G.
History
DepositionMay 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 11, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2014Group: Database references
Revision 1.2Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thymidylate kinase
B: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,8854
Polymers46,9092
Non-polymers9762
Water2,972165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2010 Å2
ΔGint-19 kcal/mol
Surface area17930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.780, 90.841, 48.221
Angle α, β, γ (deg.)90.000, 102.880, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Thymidylate kinase / / dTMP kinase


Mass: 23454.586 Da / Num. of mol.: 2 / Fragment: TMK / Mutation: none
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus subsp. aureus (bacteria)
Strain: N315 / Gene: SAR0483, tmk / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q6GJI9, dTMP kinase
#2: Chemical ChemComp-31Z / 2-(3-chlorophenoxy)-3-fluoro-4-{[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]methyl}benzoic acid


Mass: 487.908 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23ClFN3O5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 165 / Source method: isolated from a natural source / Formula: H2O

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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: 2.08 Å3/Da / Density % sol: 40.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: To obtain the inhibitor bound crystal form of TMK-S.aureus crystals were initially grown in the absence of compound using the sitting drop method at 293 K with a reservoir solution of 100 mM ...Details: To obtain the inhibitor bound crystal form of TMK-S.aureus crystals were initially grown in the absence of compound using the sitting drop method at 293 K with a reservoir solution of 100 mM PCPT (propionate-cacodylate-bistris propane buffer) pH 7-8, 21-24% PEG 3350, 200 mM Mg2Cl using 1:1 protein:reservoir solution with the protein solution at 13 mg/mL. Crystals were harvested and soaked overnight in a solution containing 100 mM PCPT, 35% PEG 3350, 200 mM Mg2Cl and 1-2 mM or compound from a 100 mM DMSO stock. After soaking the crystals were cryoprotected by soaking for 15 minutes in compound-soak solution supplemented with 20% ethylene glycol., VAPOR DIFFUSION, SITTING DROP
PH range: 7-8

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Data collection

DiffractionMean temperature: 140 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 10, 2010 / Details: monochrome
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.94→21.05 Å / Num. all: 28451 / Num. obs: 26829 / % possible obs: 94.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.5 % / Biso Wilson estimate: 29.7 Å2 / Rmerge(I) obs: 0.072 / Net I/σ(I): 17.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
1.94-2.0120.2334.12514187.7
2.01-2.092.40.2035.82742196.8
2.09-2.182.50.1872762196.9
2.18-2.32.50.1598.32732195.9
2.3-2.442.50.1459.62710195.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.11.5refinement
AMoREphasing
PHENIXrefinement
PDB_EXTRACT3.14data extraction
JDirectordata collection
PROCESSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.94→21.05 Å / Cor.coef. Fo:Fc: 0.9154 / Cor.coef. Fo:Fc free: 0.9138 / SU R Cruickshank DPI: 0.19 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2173 1365 5.09 %RANDOM
Rwork0.1919 ---
obs0.1932 26829 94.29 %-
Displacement parametersBiso max: 135.98 Å2 / Biso mean: 35.96 Å2 / Biso min: 16.94 Å2
Baniso -1Baniso -2Baniso -3
1--5.5719 Å20 Å2-13.5013 Å2
2--8.0751 Å20 Å2
3----2.5032 Å2
Refine analyzeLuzzati coordinate error obs: 0.223 Å
Refinement stepCycle: LAST / Resolution: 1.94→21.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3128 0 68 165 3361
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_angle_deg1.01
X-RAY DIFFRACTIONo_bond_d0.1
LS refinement shellResolution: 1.94→2.02 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.3078 141 4.95 %
Rwork0.221 2707 -
all0.2253 2848 -
obs--94.29 %

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