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- PDB-4q18: Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 4... -

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Basic information

Entry
Database: PDB / ID: 4q18
TitleHuman dCK C4S-S74E mutant in complex with UDP and the inhibitor 4 [1-[5-(4-{[(2,6-diaminopyrimidin-4-yl)sulfanyl]methyl}-5-propyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]-2-methylpropan-2-ol]
ComponentsDeoxycytidine kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PHOSPHORYL TRANSFER / PHOSPHORYLATION / DEOXYCYTIDINE / TRANSFERASE / INHIBITOR COMPLEX / kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


deoxycytidine kinase / 2'-deoxyadenosine kinase / deoxyguanosine kinase / dAMP salvage / deoxycytidine kinase activity / nucleoside phosphate biosynthetic process / deoxyguanosine kinase activity / deoxyadenosine kinase activity / Pyrimidine salvage / cytidine kinase activity ...deoxycytidine kinase / 2'-deoxyadenosine kinase / deoxyguanosine kinase / dAMP salvage / deoxycytidine kinase activity / nucleoside phosphate biosynthetic process / deoxyguanosine kinase activity / deoxyadenosine kinase activity / Pyrimidine salvage / cytidine kinase activity / pyrimidine nucleotide metabolic process / Purine salvage / protein homodimerization activity / mitochondrion / nucleoplasm / ATP binding / cytoplasm / cytosol
Similarity search - Function
Deoxynucleoside kinase / : / Deoxynucleoside kinase domain / Deoxynucleoside 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-2XJ / URIDINE-5'-DIPHOSPHATE / Deoxycytidine kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsNomme, J. / Lavie, A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.
Authors: Nomme, J. / Li, Z. / Gipson, R.M. / Wang, J. / Armijo, A.L. / Le, T. / Poddar, S. / Smith, T. / Santarsiero, B.D. / Nguyen, H.A. / Czernin, J. / Alexandrova, A.N. / Jung, M.E. / Radu, C.G. / Lavie, A.
History
DepositionApr 3, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 5, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 17, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)68,1148
Polymers65,4032
Non-polymers2,7116
Water1,58588
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3800 Å2
ΔGint-31 kcal/mol
Surface area20330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.750, 68.750, 122.450
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein Deoxycytidine kinase / dCK


Mass: 32701.627 Da / Num. of mol.: 2 / Mutation: C9S, C45S, C59S, S74E, C146S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DCK / Plasmid: pET14B / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3 C41 / References: UniProt: P27707, deoxycytidine kinase
#2: Chemical
ChemComp-2XJ / 1-(5-(4-(((2,6-diaminopyrimidin-4-yl)thio)methyl)-5-propylthiazol-2-yl)-2-methoxyphenoxy)-2-methylpropan-2-ol / 1-[5-(4-{[(2,6-diaminopyrimidin-4-yl)sulfanyl]methyl}-5-propyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]-2-methylpropan-2-ol


Mass: 475.627 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H29N5O3S2
#3: Chemical ChemComp-UDP / URIDINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 404.161 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H14N2O12P2 / Comment: UDP*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 88 / 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: 2.21 Å3/Da / Density % sol: 44.4 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.5 M trisodium citrate dehydrate and 25 mM HEPES pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 285K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9785 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 20, 2012
RadiationMonochromator: C111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.504
11-H, K, -L20.496
ReflectionResolution: 2→30 Å / Num. all: 38119 / Num. obs: 38119 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rsym value: 0.059 / Net I/σ(I): 13.6
Reflection shellResolution: 2→2.1 Å / Mean I/σ(I) obs: 2.75 / Num. unique all: 5189 / Rsym value: 0.547 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.8.0049refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4JLN

4jln


Resolution: 2→27.97 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.468 / SU ML: 0.075 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.036 / ESU R Free: 0.031 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21613 1924 5 %RANDOM
Rwork0.18308 ---
all0.18485 36194 --
obs0.18485 36194 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.465 Å2
Baniso -1Baniso -2Baniso -3
1--2.98 Å20 Å20 Å2
2---2.98 Å20 Å2
3---5.95 Å2
Refinement stepCycle: LAST / Resolution: 2→27.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3788 0 178 88 4054
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.024110
X-RAY DIFFRACTIONr_bond_other_d0.0050.023796
X-RAY DIFFRACTIONr_angle_refined_deg1.6561.9955597
X-RAY DIFFRACTIONr_angle_other_deg1.1053.0118707
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2955469
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.64924.422199
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.81315687
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4841521
X-RAY DIFFRACTIONr_chiral_restr0.0840.2585
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024572
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02985
X-RAY DIFFRACTIONr_mcbond_it3.0074.6381852
X-RAY DIFFRACTIONr_mcbond_other3.0064.6381851
X-RAY DIFFRACTIONr_mcangle_it4.1096.942311
X-RAY DIFFRACTIONr_mcangle_other4.1096.942312
X-RAY DIFFRACTIONr_scbond_it2.7484.7172258
X-RAY DIFFRACTIONr_scbond_other2.7474.7172259
X-RAY DIFFRACTIONr_scangle_other3.8857.043281
X-RAY DIFFRACTIONr_long_range_B_refined5.71437.284952
X-RAY DIFFRACTIONr_long_range_B_other5.70737.2674937
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.34 120 -
Rwork0.245 2701 -
obs--99.86 %

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