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- PDB-7ctz: Wild-type plasmodium falciparum dihydrofolate reductase-thymidyla... -

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Basic information

Entry
Database: PDB / ID: 7ctz
TitleWild-type plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with fragment 148, NADPH, and dUMP
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / Anti-folate / anti-malarial / plasmodium falciparum / dihydrofolate reductase / ANTIBIOTIC
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/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. ...Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily
Similarity search - Domain/homology
1-[3-(trifluoromethyl)phenyl]urea / Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsVitsupakorn, D.
Funding support Thailand, 1items
OrganizationGrant numberCountry
National Center for Genetic Engineering and Biotechnology (Thailand)P1850116 Thailand
CitationJournal: J Enzyme Inhib Med Chem / Year: 2021
Title: Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening.
Authors: Hoarau, M. / Vanichtanankul, J. / Srimongkolpithak, N. / Vitsupakorn, D. / Yuthavong, Y. / Kamchonwongpaisan, S.
History
DepositionAug 20, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)145,9677
Polymers143,6562
Non-polymers2,3115
Water1,04558
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11880 Å2
ΔGint-49 kcal/mol
Surface area45550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.638, 155.639, 164.614
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 71828.000 Da / Num. of mol.: 2 / Fragment: fragment 148
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: DHFR-TS, dhfr-ts / Production host: Escherichia coli (E. coli) / References: UniProt: A7UD81
#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N2O8P
#4: Chemical ChemComp-GF6 / 1-[3-(trifluoromethyl)phenyl]urea


Mass: 204.149 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H7F3N2O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.53 Å3/Da / Density % sol: 56.37 %
Crystal growTemperature: 297 K / Method: microbatch / pH: 4.6 / Details: 0.1M NaOAc, 0.17 M Ammonium acetate, 18% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: BRUKER D8 QUEST / Wavelength: 1.5418 Å
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: Sep 19, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.65→24.83 Å / Num. obs: 42316 / % possible obs: 97.9 % / Redundancy: 5.85 % / Rmerge(I) obs: 0.1612 / Net I/σ(I): 10.3
Reflection shellResolution: 2.65→2.7 Å / Redundancy: 4.65 % / Rmerge(I) obs: 0.5087 / Num. unique obs: 1884 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PROTEUM PLUSdata reduction
Coot0.8.9.2model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DPD

4dpd


Resolution: 2.65→24.826 Å / Cor.coef. Fo:Fc: 0.909 / Cor.coef. Fo:Fc free: 0.828 / Cross valid method: NONE / ESU R: 0.226 / ESU R Free: 0.089
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.3245 2095 4.951 %
Rwork0.255 40221 -
all0.258 --
obs-42316 97.82 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 31.691 Å2
Baniso -1Baniso -2Baniso -3
1--0.229 Å20 Å20 Å2
2---3.457 Å2-0 Å2
3---3.686 Å2
Refinement stepCycle: LAST / Resolution: 2.65→24.826 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8867 0 158 58 9083
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0139256
X-RAY DIFFRACTIONr_bond_other_d0.0350.0178376
X-RAY DIFFRACTIONr_angle_refined_deg1.8431.64512524
X-RAY DIFFRACTIONr_angle_other_deg2.3421.57919512
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.03751057
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.623.794506
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.155151655
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5331536
X-RAY DIFFRACTIONr_chiral_restr0.0770.21188
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0210103
X-RAY DIFFRACTIONr_gen_planes_other0.0110.021955
X-RAY DIFFRACTIONr_nbd_refined0.2190.21863
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2230.28225
X-RAY DIFFRACTIONr_nbtor_refined0.180.24254
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0760.23994
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.190.2242
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1410.211
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2770.213
X-RAY DIFFRACTIONr_nbd_other0.270.245
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1380.26
X-RAY DIFFRACTIONr_mcbond_it3.1073.3224255
X-RAY DIFFRACTIONr_mcbond_other3.1073.3214254
X-RAY DIFFRACTIONr_mcangle_it5.0624.9585303
X-RAY DIFFRACTIONr_mcangle_other5.0624.9595304
X-RAY DIFFRACTIONr_scbond_it2.8813.4835001
X-RAY DIFFRACTIONr_scbond_other2.8813.4844998
X-RAY DIFFRACTIONr_scangle_it4.7285.127221
X-RAY DIFFRACTIONr_scangle_other4.7285.127222
X-RAY DIFFRACTIONr_lrange_it7.34736.410134
X-RAY DIFFRACTIONr_lrange_other7.34736.40210133
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.7190.6581620.5493011X-RAY DIFFRACTION99.7799
2.719-2.7930.4651260.4652905X-RAY DIFFRACTION100
2.793-2.8740.6151330.3972849X-RAY DIFFRACTION99.9665
2.874-2.9630.4141750.3792743X-RAY DIFFRACTION100
2.963-3.060.3511580.3182652X-RAY DIFFRACTION100
3.06-3.1670.411340.32611X-RAY DIFFRACTION99.9272
3.167-3.2870.3521440.2632451X-RAY DIFFRACTION98.8571
3.287-3.4210.3161220.2542316X-RAY DIFFRACTION96.5927
3.421-3.5730.2631220.212197X-RAY DIFFRACTION94.23
3.573-3.7470.2811130.2332020X-RAY DIFFRACTION91.5058
3.747-3.950.2481060.21947X-RAY DIFFRACTION91.9803
3.95-4.1890.232840.2011952X-RAY DIFFRACTION96.0377
4.189-4.4780.253840.1951899X-RAY DIFFRACTION99.1005
4.478-4.8370.229850.1681777X-RAY DIFFRACTION99.7322
4.837-5.2980.216720.1641651X-RAY DIFFRACTION99.8841
5.298-5.9220.274720.1981493X-RAY DIFFRACTION99.8724
5.922-6.8370.342750.2051328X-RAY DIFFRACTION99.9288
6.837-8.370.225460.1771162X-RAY DIFFRACTION100
8.37-11.8220.236560.16901X-RAY DIFFRACTION100
11.822-24.8260.345260.314356X-RAY DIFFRACTION67.2535

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