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- PDB-3uwk: Structure Guided Development of Novel Thymidine Mimetics targetin... -

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Basic information

Entry
Database: PDB / ID: 3uwk
TitleStructure Guided Development of Novel Thymidine Mimetics targeting Pseudomonas aeruginosa Thymidylate Kinase: from Hit to Lead Generation
ComponentsThymidylate kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Thymidylate kinase / kinase / thymidine triphosphate / 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 / cytoplasm
Similarity search - Function
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-0DF / Thymidylate kinase
Similarity search - Component
Biological speciesPseudomonas aeruginosa (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.91 Å
AuthorsChoi, J.Y. / Plummer, M.S. / Starr, J. / Desbonnet, C.R. / Soutter, H.H. / Chang, J. / Miller, J.R. / Dillman, K. / Miller, A.A. / Roush, W.R.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Structure guided development of novel thymidine mimetics targeting Pseudomonas aeruginosa thymidylate kinase: from hit to lead generation.
Authors: Choi, J.Y. / Plummer, M.S. / Starr, J. / Desbonnet, C.R. / Soutter, H. / Chang, J. / Miller, J.R. / Dillman, K. / Miller, A.A. / Roush, W.R.
History
DepositionDec 2, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2012Group: 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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)51,3785
Polymers50,9042
Non-polymers4753
Water1,78399
1
A: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,7013
Polymers25,4521
Non-polymers2502
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6772
Polymers25,4521
Non-polymers2251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Thymidylate kinase
hetero molecules

B: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,3785
Polymers50,9042
Non-polymers4753
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area2330 Å2
ΔGint-16 kcal/mol
Surface area16650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.341, 118.063, 41.918
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-256-

HOH

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Components

#1: Protein Thymidylate kinase / dTMP kinase


Mass: 25451.842 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Pseudomonas aeruginosa (bacteria) / Strain: ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228 / Gene: PA2962, tmk / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3 / References: UniProt: Q9HZN8, dTMP kinase
#2: Chemical ChemComp-0DF / 1-methyl-6-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one


Mass: 225.246 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H11N3O
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 1.81 Å3/Da / Density % sol: 31.93 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: The protein was mixed 1:1 with a reservoir solution containing 30% PEG 4000, 0.2M MgCl2, and 0.1 M Tris pH 7.5 - 8.5 and incubated at 295, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jan 1, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→62.87 Å / Num. all: 29391 / Num. obs: 110874 / % possible obs: 99.7 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Rsym value: 0.069 / Net I/σ(I): 18.7
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 2.6 / Num. unique all: 2876 / Rsym value: 0.443 / % possible all: 100

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Processing

Software
NameVersionClassification
JDirectordata collection
MOLREPphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.91→62.87 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.932 / SU B: 3.501 / SU ML: 0.105 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.175 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2424 1489 5.1 %RANDOM
Rwork0.19455 ---
all0.19688 29391 --
obs0.19688 27872 99.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.215 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å20 Å20 Å2
2---0.16 Å20 Å2
3---1.04 Å2
Refinement stepCycle: LAST / Resolution: 1.91→62.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3076 0 35 99 3210
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0223167
X-RAY DIFFRACTIONr_angle_refined_deg1.7422.0134293
X-RAY DIFFRACTIONr_dihedral_angle_1_deg21.7285395
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.00822.564156
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.15715512
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.6381544
X-RAY DIFFRACTIONr_chiral_restr0.1610.2477
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022474
X-RAY DIFFRACTIONr_nbd_refined0.240.21412
X-RAY DIFFRACTIONr_nbtor_refined0.3210.22167
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1320.2152
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2790.2108
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.120.217
X-RAY DIFFRACTIONr_mcbond_it2.0771.52035
X-RAY DIFFRACTIONr_mcangle_it2.9823141
X-RAY DIFFRACTIONr_scbond_it4.65531270
X-RAY DIFFRACTIONr_scangle_it6.7074.51152
LS refinement shellResolution: 1.908→1.957 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.262 109 -
Rwork0.213 1933 -
obs--96.05 %

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