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- PDB-4hld: Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Po... -

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Basic information

Entry
Database: PDB / ID: 4hld
TitleSulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 11
ComponentsThymidylate kinase
Keywordstransferase/transferase inhibitor / TMK / kinase / thymidylate kinase / MRSA / pipiridine / transferase-transferase inhibitor complex
Function / homology
Function and homology information


dTMP kinase / dUDP biosynthetic process / dTDP biosynthetic process / dTMP kinase activity / dTTP biosynthetic process / ATP binding / cytosol
Similarity search - Function
Thymidylate kinase, conserved site / Thymidylate kinase signature. / Thymidylate kinase / Thymidylate kinase-like domain / Thymidylate kinase / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-16T / Thymidylate kinase
Similarity search - Component
Biological speciesStaphylococcus aureus subsp. aureus (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsOlivier, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).
Authors: Martinez-Botella, G. / Loch, J.T. / Green, O.M. / Kawatkar, S.P. / Olivier, N.B. / Boriack-Sjodin, P.A. / Keating, T.A.
History
DepositionOct 16, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Feb 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)47,8934
Polymers46,9092
Non-polymers9842
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1990 Å2
ΔGint-19 kcal/mol
Surface area17660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.490, 90.498, 47.803
Angle α, β, γ (deg.)90.00, 104.05, 90.00
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus subsp. aureus (bacteria)
Strain: MRSA252 / Gene: SAR0483, tmk / Plasmid: pET30 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) codon + / References: UniProt: Q6GJI9, dTMP kinase
#2: Chemical ChemComp-16T / 1-[(3S)-1-{[3-(3-chlorophenoxy)-4-hydroxyphenyl]sulfonyl}piperidin-3-yl]-5-methylpyrimidine-2,4(1H,3H)-dione


Mass: 491.945 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22ClN3O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 2.03 Å3/Da / Density % sol: 39.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8
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 TK-666 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. Cryoprotected crystals were mounted on nylon loops and flash-cooled in liquid nitrogen., VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Nov 23, 2009 / Details: Microfocus rotating anode with 70 uM focal spot.
RadiationMonochromator: Varimax confocal X-ray optical assembly / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 25368 / Num. obs: 23390 / % possible obs: 92.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.4 % / Biso Wilson estimate: 30.73 Å2 / Rmerge(I) obs: 0.067 / Net I/σ(I): 12.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2-2.072.40.4012.1195.6
2.07-2.152.40.312.8196
2.15-2.252.40.2193.3196
2.25-2.372.40.1793.5164.5
2.37-2.522.30.164.7191.3
2.52-2.712.30.1255.9190
2.71-2.992.20.0968.1185.7
2.99-3.422.30.06312.7185.5
3.42-4.312.60.04522.7192.8
4.31-502.90.03334.4195.2

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Processing

Software
NameVersionClassification
APEXdata collection
AMoREphasing
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→17.92 Å / Cor.coef. Fo:Fc: 0.9263 / Cor.coef. Fo:Fc free: 0.9086 / SU R Cruickshank DPI: 0.248 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: Data reduction was accomplished by employing the AutoPROC toolbox and the structure determined by molecular replacement with AMoRE using an apo-state model of S. aureus TMK. COOT was used to ...Details: Data reduction was accomplished by employing the AutoPROC toolbox and the structure determined by molecular replacement with AMoRE using an apo-state model of S. aureus TMK. COOT was used to inspect the model and electron density and BUSTER or REFMAC were used for macromolecular refinement calculations. Geometry of the model was analyzed with MolProbity and stereochemistry of the compound analyzed with MOGUL.
RfactorNum. reflection% reflectionSelection details
Rfree0.2387 1185 5.08 %RANDOM
Rwork0.2078 ---
obs0.2094 23315 91.88 %-
all-25375 --
Displacement parametersBiso mean: 34.4 Å2
Baniso -1Baniso -2Baniso -3
1--3.3216 Å20 Å2-9.3453 Å2
2--6.9404 Å20 Å2
3----3.6188 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 2→17.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3111 0 66 174 3351
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013231HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.094375HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1139SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes90HARMONIC2
X-RAY DIFFRACTIONt_gen_planes478HARMONIC5
X-RAY DIFFRACTIONt_it3231HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion19.25
X-RAY DIFFRACTIONt_chiral_improper_torsion423SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3936SEMIHARMONIC4
LS refinement shellResolution: 2→2.09 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2614 142 4.9 %
Rwork0.2454 2754 -
all0.2462 2896 -
obs--91.88 %

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