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- PDB-8wgm: Quadruple mutant Plasmodium falciparum dihydrofolate reductase-th... -

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Basic information

Entry
Database: PDB / ID: 8wgm
TitleQuadruple mutant Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS V1/S, N51I+C59R+S108N+I164L) complexed with LA1, NADPH and dUMP
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / DHFR / dihydrofolate reductase / Plasmodium falciparum / malaria
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, 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 conserved site / Dihydrofolate reductase (DHFR) domain signature. ...Bifunctional dihydrofolate reductase/thymidylate synthase / 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 conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase-like domain superfamily
Similarity search - Domain/homology
Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / : / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum VS/1 (eukaryote)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsVanichtanankul, J. / Saeyang, T. / Vitsupakorn, D. / Arwon, U. / Decharuangsilp, S. / Yuthavong, Y. / Kamchonwongpaisan, S.
Funding support Thailand, 1items
OrganizationGrant numberCountry
National Science and Technology Development Agency (NSTDA)P1850116 Thailand
CitationJournal: Bioorg.Chem. / Year: 2024
Title: Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors.
Authors: Decharuangsilp, S. / Arwon, U. / Hoarau, M. / Vanichtanankul, J. / Saeyang, T. / Jantra, T. / Rattanajak, R. / Thiabma, R. / Sooksai, N. / Kongkasuriyachai, D. / Kamchonwongpaisan, S. / Yuthavong, Y.
History
DepositionSep 22, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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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)146,4888
Polymers143,6122
Non-polymers2,8766
Water13,944774
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11450 Å2
ΔGint-47 kcal/mol
Surface area44360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.355, 156.283, 165.000
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 71805.953 Da / Num. of mol.: 2 / Mutation: N51I,C59R,S108N,I164L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum VS/1 (eukaryote) / Gene: DHFR-TS / Production host: Escherichia coli BL21(DE3) (bacteria) / 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-WCQ / (3~{E})-3-[[2-[3-[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]oxypropoxy]phenyl]methylidene]oxolan-2-one


Mass: 384.429 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H24N4O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 774 / 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: 2.62 Å3/Da / Density % sol: 53.05 %
Description: The entry contains friedel pairs in I_plus/minus columns
Crystal growTemperature: 297 K / Method: microbatch / pH: 5 / Details: 0.1M Na malonate, 17% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: Cu FINE FOCUS / Wavelength: 1.5418 Å
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: Sep 8, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.15→24.32 Å / Num. obs: 157173 / % possible obs: 99.7 % / Redundancy: 6.15 % / Biso Wilson estimate: 25.25 Å2 / CC1/2: 0.997 / Net I/σ(I): 11.9
Reflection shellResolution: 2.15→2.227 Å / Redundancy: 4.65 % / Rmerge(I) obs: 0.672 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 8138 / CC1/2: 0.761

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Cootmodel building
PROTEUM PLUSdata collection
PROTEUM PLUSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→24.32 Å / SU ML: 0.253 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 23.925
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Details: The entry contains friedel pairs in I_plus/minus columns
RfactorNum. reflection% reflection
Rfree0.233 3816 2.43 %
Rwork0.1901 153357 -
obs0.1912 157173 99.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.62 Å2
Refinement stepCycle: LAST / Resolution: 2.15→24.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8814 0 192 774 9780
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00789226
X-RAY DIFFRACTIONf_angle_d0.950112486
X-RAY DIFFRACTIONf_chiral_restr0.05551339
X-RAY DIFFRACTIONf_plane_restr0.00721567
X-RAY DIFFRACTIONf_dihedral_angle_d15.67683412
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.180.31471500.28155444X-RAY DIFFRACTION95.72
2.18-2.210.31411340.26185550X-RAY DIFFRACTION97.06
2.21-2.240.28821260.26855686X-RAY DIFFRACTION97.73
2.24-2.270.29091290.2935592X-RAY DIFFRACTION97.31
2.27-2.30.28341420.26275599X-RAY DIFFRACTION98.85
2.3-2.340.26461450.24655729X-RAY DIFFRACTION99.66
2.34-2.380.31871660.2415635X-RAY DIFFRACTION99.71
2.38-2.420.28171320.24375777X-RAY DIFFRACTION99.85
2.42-2.460.31071360.2345690X-RAY DIFFRACTION99.85
2.46-2.510.3181330.22865719X-RAY DIFFRACTION99.88
2.51-2.560.32121440.23155756X-RAY DIFFRACTION99.92
2.56-2.610.26141460.22365698X-RAY DIFFRACTION99.93
2.61-2.680.27161420.22115735X-RAY DIFFRACTION99.86
2.68-2.740.26881400.21455716X-RAY DIFFRACTION99.98
2.74-2.820.28591520.20915700X-RAY DIFFRACTION99.95
2.82-2.90.25651480.20545761X-RAY DIFFRACTION99.98
2.9-2.990.24771390.19675671X-RAY DIFFRACTION99.95
2.99-3.10.25641350.20475738X-RAY DIFFRACTION99.83
3.1-3.220.22421510.19565737X-RAY DIFFRACTION99.88
3.22-3.370.23231390.185710X-RAY DIFFRACTION99.8
3.37-3.550.22421290.16945756X-RAY DIFFRACTION99.83
3.55-3.770.23661510.16595664X-RAY DIFFRACTION99.81
3.77-4.060.16711360.15285753X-RAY DIFFRACTION99.88
4.06-4.460.16291530.13075735X-RAY DIFFRACTION99.98
4.46-5.10.16391420.13435686X-RAY DIFFRACTION99.95
5.1-6.410.20781440.1635725X-RAY DIFFRACTION100
6.41-24.320.17591320.15425395X-RAY DIFFRACTION94.17

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