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

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Basic information

Entry
Database: PDB / ID: 3uxm
TitleStructure Guided Development of Novel Thymidine Mimetics targeting Pseudomonas aeruginosa Thymidylate Kinase: from Hit to Lead Generation
ComponentsThymidylate kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Thymidylate kinase / thymidine triphosphate / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


dUDP biosynthetic process / dTMP kinase / thymidylate kinase activity / dTDP biosynthetic process / 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
5'-deoxy-5'-fluorothymidine / Thymidylate kinase
Similarity search - Component
Biological speciesPseudomonas aeruginosa (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 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 5, 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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
C: Thymidylate kinase
D: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,67112
Polymers92,5974
Non-polymers1,0748
Water6,792377
1
A: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,4424
Polymers23,1491
Non-polymers2933
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,3932
Polymers23,1491
Non-polymers2441
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,4424
Polymers23,1491
Non-polymers2933
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,3932
Polymers23,1491
Non-polymers2441
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
A: Thymidylate kinase
hetero molecules

B: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8366
Polymers46,2992
Non-polymers5374
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area2260 Å2
ΔGint-25 kcal/mol
Surface area17410 Å2
MethodPISA
6
C: Thymidylate kinase
D: Thymidylate kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8366
Polymers46,2992
Non-polymers5374
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2330 Å2
ΔGint-25 kcal/mol
Surface area17000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.877, 41.544, 117.886
Angle α, β, γ (deg.)90.00, 90.02, 90.00
Int Tables number3
Space group name H-MP121
Components on special symmetry positions
IDModelComponents
11C-374-

HOH

21D-373-

HOH

31D-375-

HOH

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Components

#1: Protein
Thymidylate kinase / dTMP kinase


Mass: 23149.273 Da / Num. of mol.: 4 / Fragment: Kinase domain
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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Fragment: Kinase domain / Source method: obtained synthetically / Formula: Mg / References: dTMP kinase
#3: Chemical
ChemComp-0DN / 5'-deoxy-5'-fluorothymidine


Mass: 244.220 Da / Num. of mol.: 4 / Fragment: Kinase domain / Source method: obtained synthetically / Formula: C10H13FN2O4 / References: dTMP kinase
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 377 / Fragment: Kinase domain / Source method: isolated from a natural source / Formula: H2O / References: dTMP kinase

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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: 1.95 Å3/Da / Density % sol: 37.04 %
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 295K, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ DW / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jan 1, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.95→24.6 Å / Num. all: 51360 / Num. obs: 177972 / % possible obs: 97.5 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.5 % / Rsym value: 0.064 / Net I/σ(I): 15.5
Reflection shellResolution: 1.95→2.2 Å / Redundancy: 3 % / Mean I/σ(I) obs: 3.32 / Num. unique all: 4746 / Rsym value: 0.323 / % possible all: 90.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
PHASERphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→24.6 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.923 / SU B: 3.95 / SU ML: 0.116 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.194 / ESU R Free: 0.175 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23575 2620 5.1 %RANDOM
Rwork0.17506 ---
all0.17817 51360 --
obs0.17817 48710 97.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.164 Å2
Baniso -1Baniso -2Baniso -3
1--0.5 Å20 Å2-0.19 Å2
2--0.25 Å20 Å2
3---0.25 Å2
Refinement stepCycle: LAST / Resolution: 1.95→24.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6224 0 72 377 6673
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0226421
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.622.0128707
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg21.0925801
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.32122.39318
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.706151041
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5471593
X-RAY DIFFRACTIONr_chiral_restr0.1360.2982
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024985
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2290.23009
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3140.24392
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2357
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2280.2142
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.180.237
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.9061.54123
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.71726365
X-RAY DIFFRACTIONr_scbond_it4.49132529
X-RAY DIFFRACTIONr_scangle_it6.2374.52342
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 139 -
Rwork0.211 3132 -
obs--84.54 %

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