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- PDB-3kjs: Crystal Structure of T. cruzi DHFR-TS with 3 high affinity DHFR i... -

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Basic information

Entry
Database: PDB / ID: 3kjs
TitleCrystal Structure of T. cruzi DHFR-TS with 3 high affinity DHFR inhibitors: DQ1 inhibitor complex
ComponentsDihydrofolate reductase-thymidylate synthase
KeywordsOxidoreductase / Transferase
Function / homology
Function and homology information


thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / nucleotide binding / mitochondrion / cytosol
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase ...Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-DQ1 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesTrypanosoma cruzi (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSchormann, N. / Senkovich, O. / Chattopadhyay, D.
CitationJournal: Bioorg.Med.Chem. / Year: 2010
Title: Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase.
Authors: Schormann, N. / Velu, S.E. / Murugesan, S. / Senkovich, O. / Walker, K. / Chenna, B.C. / Shinkre, B. / Desai, A. / Chattopadhyay, D.
History
DepositionNov 3, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 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_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: Dihydrofolate reductase-thymidylate synthase
B: Dihydrofolate reductase-thymidylate synthase
C: Dihydrofolate reductase-thymidylate synthase
D: Dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)241,86733
Polymers235,6164
Non-polymers6,25129
Water13,277737
1
A: Dihydrofolate reductase-thymidylate synthase
D: Dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,02718
Polymers117,8082
Non-polymers3,21916
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4340 Å2
ΔGint-10 kcal/mol
Surface area42730 Å2
MethodPISA
2
B: Dihydrofolate reductase-thymidylate synthase
C: Dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,84115
Polymers117,8082
Non-polymers3,03213
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4310 Å2
ΔGint-10 kcal/mol
Surface area43540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)175.620, 175.620, 249.905
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Dihydrofolate reductase-thymidylate synthase


Mass: 58904.074 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma cruzi (eukaryote) / Strain: Y / Gene: dhfrts / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3)pLysS
References: UniProt: Q8T5T8, dihydrofolate reductase, thymidylate synthase

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Non-polymers , 5 types, 766 molecules

#2: Chemical
ChemComp-DQ1 / ethyl 4-(5-{[(2,4-diaminoquinazolin-6-yl)methyl]amino}-2-methoxyphenoxy)butanoate


Mass: 425.481 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H27N5O4
#3: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 737 / 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: 4.11 Å3/Da / Density % sol: 70.08 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 50mM Hepes, pH 7.0, 10mM magnesium chloride, 1.5-1.7M ammonium sulfate, 5-10% ethylene glycol, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Aug 15, 2006 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→20 Å / Num. all: 134571 / Num. obs: 134571 / % possible obs: 99.6 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 4 % / Biso Wilson estimate: 35.3 Å2 / Rmerge(I) obs: 0.06 / Rsym value: 0.06 / Net I/σ(I): 13
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.256 / Mean I/σ(I) obs: 4 / Rsym value: 0.256 / % possible all: 98.9

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.5.0102refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2H2Q

2h2q


Resolution: 2.5→20 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.926 / SU B: 14.628 / SU ML: 0.153 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / ESU R: 0.275 / ESU R Free: 0.218 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23378 6726 5 %RANDOM
Rwork0.19999 ---
obs0.20167 126968 99.57 %-
all-127341 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.712 Å2
Baniso -1Baniso -2Baniso -3
1-1.18 Å20 Å20 Å2
2--1.18 Å20 Å2
3----2.36 Å2
Refinement stepCycle: LAST / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15905 0 408 737 17050
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.02216700
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1831.99222681
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.36652003
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.84822.737760
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.648152689
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.59515158
X-RAY DIFFRACTIONr_chiral_restr0.0950.22458
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02112730
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3851.510015
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.745216157
X-RAY DIFFRACTIONr_scbond_it0.94736685
X-RAY DIFFRACTIONr_scangle_it1.6574.56523
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 475 -
Rwork0.27 9160 -
obs--99.74 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.5133-0.2750.77950.2932-0.36482.0083-0.0684-0.03840.10280.0485-0.0270.061-0.3195-0.2260.09540.09540.02560.01780.1016-0.04240.136531.2520.84548.578
20.52770.2314-0.42580.4815-0.31791.7602-0.0006-0.0611-0.08670.0363-0.02590.130.2873-0.26120.02640.0949-0.05-0.0070.0891-0.01060.115529.252-14.75918.054
30.71560.33760.6760.81350.72591.9355-0.06110.0380.1057-0.07310.0047-0.0661-0.26210.18670.05650.0417-0.02510.00370.03150.0240.063959.62420.08318.774
40.5392-0.2743-0.44880.82440.6931.7648-0.0232-0.0414-0.07410.0505-0.021-0.05050.24970.13110.04430.05630.0112-0.00110.03640.0350.053557.587-16.63347.937
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 232
2X-RAY DIFFRACTION1A233 - 515
3X-RAY DIFFRACTION2B3 - 232
4X-RAY DIFFRACTION2B233 - 515
5X-RAY DIFFRACTION3C2 - 232
6X-RAY DIFFRACTION3C233 - 515
7X-RAY DIFFRACTION4D2 - 232
8X-RAY DIFFRACTION4D233 - 515

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