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- PDB-8jfc: V1/S quadruple mutant Plasmodium falciparum dihydrofolate reducta... -

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Basic information

Entry
Database: PDB / ID: 8jfc
TitleV1/S quadruple mutant Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with compound 6 (B21591), 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
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 domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily
Similarity search - Domain/homology
Chem-NDP / Chem-U8I / 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: 2.3 Å
AuthorsVanichtanankul, J. / Saeyang, T. / Vitsupakorn, D. / Saepua, S. / Thongpanchang, C. / Yuthavong, Y. / Kamchonwongpaisan, S. / Hoarau, M.
Funding support Thailand, 1items
OrganizationGrant numberCountry
National Center for Genetic Engineering and Biotechnology (Thailand)P1850116 Thailand
CitationJournal: Rsc Med Chem / Year: 2023
Title: Discovery of rigid biphenyl Plasmodium falciparum DHFR inhibitors using a fragment linking strategy.
Authors: Hoarau, M. / Sermmai, P. / Varatthan, T. / Thiabma, R. / Jantra, T. / Rattanajak, R. / Vitsupakorn, D. / Vanichtanankul, J. / Saepua, S. / Yuthavong, Y. / Thongpanchang, C. / Kamchonwongpaisan, S.
History
DepositionMay 17, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 23, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: 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_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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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)146,80410
Polymers143,8162
Non-polymers2,9888
Water11,566642
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12540 Å2
ΔGint-48 kcal/mol
Surface area43550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.978, 155.757, 165.044
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

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Protein , 1 types, 2 molecules AB

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 71908.133 Da / Num. of mol.: 2 / Mutation: N51I, C59R, S108N, I164L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: DHFR-TS, V1/S / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: D9N170

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Non-polymers , 5 types, 650 molecules

#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-U8I / 4-[3-[[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]methyl]phenyl]benzoic acid


Mass: 348.398 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 642 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.93 Å3/Da / Density % sol: 58.07 %
Crystal growTemperature: 297 K / Method: microbatch / pH: 4.6 / Details: PEG4000, ammonium acetate, sodium acetate

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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: Mar 24, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→24.31 Å / Num. obs: 65658 / % possible obs: 99.1 % / Redundancy: 3.52 % / Biso Wilson estimate: 24.95 Å2 / Rmerge(I) obs: 0.0862 / Net I/σ(I): 10.06
Reflection shellResolution: 2.3→2.4 Å / Rmerge(I) obs: 0.2639 / Num. unique obs: 6385

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PROTEUM PLUSdata reduction
PROTEUM PLUSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DP3

4dp3


Resolution: 2.3→24.31 Å / SU ML: 0.2723 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 23.5091
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2378 3445 5.25 %
Rwork0.1876 62213 -
obs0.1903 65658 99.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.15 Å2
Refinement stepCycle: LAST / Resolution: 2.3→24.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8807 0 200 642 9649
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00799225
X-RAY DIFFRACTIONf_angle_d0.946712486
X-RAY DIFFRACTIONf_chiral_restr0.05591337
X-RAY DIFFRACTIONf_plane_restr0.00751568
X-RAY DIFFRACTIONf_dihedral_angle_d15.60373404
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.330.2921360.22642422X-RAY DIFFRACTION97.52
2.33-2.360.30131280.2342424X-RAY DIFFRACTION97.33
2.36-2.40.26541350.24142415X-RAY DIFFRACTION99.03
2.4-2.440.28671440.23952435X-RAY DIFFRACTION98.93
2.44-2.480.26621440.21632483X-RAY DIFFRACTION99.47
2.48-2.520.29211470.21432414X-RAY DIFFRACTION99.3
2.52-2.570.28681300.21662467X-RAY DIFFRACTION99.2
2.57-2.620.27951250.21422485X-RAY DIFFRACTION99.81
2.62-2.670.26571340.21512467X-RAY DIFFRACTION99.88
2.67-2.730.27541430.21232510X-RAY DIFFRACTION99.85
2.73-2.790.29411340.20282459X-RAY DIFFRACTION99.88
2.79-2.860.27681360.21012511X-RAY DIFFRACTION99.92
2.86-2.940.27331440.20282467X-RAY DIFFRACTION99.89
2.94-3.020.26841300.21122494X-RAY DIFFRACTION99.92
3.02-3.120.2991300.20812504X-RAY DIFFRACTION99.81
3.12-3.230.24431210.20352500X-RAY DIFFRACTION99.89
3.23-3.360.25111240.19122537X-RAY DIFFRACTION99.85
3.36-3.510.22531230.18872499X-RAY DIFFRACTION99.62
3.51-3.70.21861350.1772506X-RAY DIFFRACTION99.21
3.7-3.930.19251500.16562482X-RAY DIFFRACTION99.32
3.93-4.230.21321380.15752508X-RAY DIFFRACTION99.06
4.23-4.650.16771570.14242500X-RAY DIFFRACTION99.18
4.65-5.320.19871380.1482568X-RAY DIFFRACTION99.67
5.32-6.680.22581710.18092567X-RAY DIFFRACTION100
6.68-24.310.20821480.17012589X-RAY DIFFRACTION95.37

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