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- PDB-5t0l: Crystal structure of Toxoplasma gondii TS-DHFR complexed with NAD... -

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Basic information

Entry
Database: PDB / ID: 5t0l
TitleCrystal structure of Toxoplasma gondii TS-DHFR complexed with NADPH, dUMP, PDDF and 5-(4-(3,4-dichlorophenyl)piperazin-1-yl)pyrimidine-2,4-diamine (TRC-15)
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOxidoreductase/Oxidoreductase inhibitor / Toxoplasma gondii / DHFR / inhibitor / Oxidoreductase-Oxidoreductase inhibitor complex
Function / homology
Function and homology information


thymidylate synthase / thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / 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-73X / 10-PROPARGYL-5,8-DIDEAZAFOLIC ACID / Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesToxoplasma gondii (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.13 Å
AuthorsThomas, S.B. / Chen, Z. / Lu, H. / Li, Y.
CitationJournal: ACS Med Chem Lett / Year: 2016
Title: Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design.
Authors: Welsch, M.E. / Zhou, J. / Gao, Y. / Yan, Y. / Porter, G. / Agnihotri, G. / Li, Y. / Lu, H. / Chen, Z. / Thomas, S.B.
History
DepositionAug 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 28, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,16910
Polymers128,4292
Non-polymers3,7418
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12130 Å2
ΔGint-62 kcal/mol
Surface area39660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.277, 143.983, 170.214
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase / DHFR-TS


Mass: 64214.312 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Production host: Escherichia coli (E. coli)
References: UniProt: Q07422, dihydrofolate reductase, thymidylate synthase
#2: Chemical ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Chemical ChemComp-CB3 / 10-PROPARGYL-5,8-DIDEAZAFOLIC ACID


Mass: 477.469 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23N5O6
#5: Chemical ChemComp-73X / 5-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyrimidine-2,4-diamine


Mass: 339.223 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16Cl2N6

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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: 2.38 Å3/Da / Density % sol: 48.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.3 / Details: PEG3350, sodium citrate dibasic

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97915 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 4, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 3.12→50 Å / Num. obs: 21429 / % possible obs: 92.4 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.127 / Net I/σ(I): 11.4
Reflection shellResolution: 3.12→3.23 Å / Rmerge(I) obs: 0.55

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
Blu-Icedata collection
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EIL

4eil


Resolution: 3.13→109.93 Å / Cor.coef. Fo:Fc: 0.894 / Cor.coef. Fo:Fc free: 0.882 / SU B: 26.524 / SU ML: 0.462 / Cross valid method: THROUGHOUT / ESU R Free: 0.577 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.27423 1101 5.1 %RANDOM
Rwork0.25257 ---
obs0.25372 20296 92.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 75.628 Å2
Baniso -1Baniso -2Baniso -3
1-1.79 Å2-0 Å20 Å2
2---6.6 Å20 Å2
3---4.81 Å2
Refinement stepCycle: LAST / Resolution: 3.13→109.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8142 0 250 0 8392
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0198628
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0811.98611722
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.31951012
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.85923.182396
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.866151412
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.281568
X-RAY DIFFRACTIONr_chiral_restr0.0660.21266
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0216570
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_it1.9867.5344078
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.4611.2825082
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.0597.5314550
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined7.89161.86312881
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.125→3.206 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 82 -
Rwork0.336 1507 -
obs--92.98 %

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