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- PDB-6leu: Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum di... -

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Basic information

Entry
Database: PDB / ID: 6leu
TitleQuadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with compound 42 and NADPH
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / Inhinitor / antifolate / dyhydrofolate reductase / plasmodium falciparum / 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, 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 ...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, 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 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-E9X / Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsVanichtanankul, J. / Vitsupakorn, D.
Funding support Thailand, 1items
OrganizationGrant numberCountry
National Center for Genetic Engineering and Biotechnology (Thailand) Thailand
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Flexible diaminodihydrotriazine inhibitors of Plasmodium falciparum dihydrofolate reductase: Binding strengths, modes of binding and their antimalarial activities.
Authors: Kamchonwongpaisan, S. / Charoensetakul, N. / Srisuwannaket, C. / Taweechai, S. / Rattanajak, R. / Vanichtanankul, J. / Vitsupakorn, D. / Arwon, U. / Thongpanchang, C. / Tarnchompoo, B. / ...Authors: Kamchonwongpaisan, S. / Charoensetakul, N. / Srisuwannaket, C. / Taweechai, S. / Rattanajak, R. / Vanichtanankul, J. / Vitsupakorn, D. / Arwon, U. / Thongpanchang, C. / Tarnchompoo, B. / Vilaivan, T. / Yuthavong, Y.
History
DepositionNov 27, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)146,7538
Polymers143,8162
Non-polymers2,9376
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11940 Å2
ΔGint-47 kcal/mol
Surface area45020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.308, 154.488, 163.939
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: 71908.133 Da / Num. of mol.: 2
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 (E. coli) / References: UniProt: D9N170
#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-E9X / 1-[3-[(4-chlorophenyl)-(phenylmethyl)amino]propoxy]-6,6-dimethyl-1,3,5-triazine-2,4-diamine


Mass: 414.932 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27ClN6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / 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: 2.61 Å3/Da / Density % sol: 52.83 %
Crystal growTemperature: 298 K / Method: microbatch / pH: 4.6
Details: 0.1M sodium acetate, pH 4.6, 0.2M ammonium acetate, 25% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418 Å
DetectorType: Nonius Kappa CCD / Detector: CCD / Date: Oct 9, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.59→10 Å / Num. obs: 40994 / % possible obs: 90.8 % / Redundancy: 3.99 % / Rmerge(I) obs: 0.071 / Net I/σ(I): 14.5
Reflection shellResolution: 2.65→2.74 Å / Rmerge(I) obs: 0.479 / Num. unique obs: 5900

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
DENZOdata reduction
Cootmodel building
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DP3

4dp3


Resolution: 2.59→10 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.882 / SU B: 11.962 / SU ML: 0.252 / Cross valid method: NONE / ESU R: 1.347 / ESU R Free: 0.352
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2609 2053 5.109 %
Rwork0.1889 --
all0.193 --
obs-40185 88.369 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 39.937 Å2
Baniso -1Baniso -2Baniso -3
1-1.514 Å20 Å2-0 Å2
2---1.818 Å20 Å2
3---0.304 Å2
Refinement stepCycle: LAST / Resolution: 2.59→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8875 0 194 123 9192
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0139291
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178431
X-RAY DIFFRACTIONr_angle_refined_deg1.791.66912575
X-RAY DIFFRACTIONr_angle_other_deg1.2591.59919618
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.07851057
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.27823.686510
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.19151652
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4881538
X-RAY DIFFRACTIONr_chiral_restr0.1160.21191
X-RAY DIFFRACTIONr_chiral_restr_other0.7530.218
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0210105
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021987
X-RAY DIFFRACTIONr_nbd_refined0.2150.21873
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1890.28609
X-RAY DIFFRACTIONr_nbtor_refined0.180.24327
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.24369
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1620.2278
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0030.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2220.226
X-RAY DIFFRACTIONr_nbd_other0.240.260
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1530.23
X-RAY DIFFRACTIONr_mcbond_it3.9724.1674252
X-RAY DIFFRACTIONr_mcbond_other3.9654.1664251
X-RAY DIFFRACTIONr_mcangle_it6.4046.2245301
X-RAY DIFFRACTIONr_mcangle_other6.4046.2255302
X-RAY DIFFRACTIONr_scbond_it3.5444.45039
X-RAY DIFFRACTIONr_scbond_other3.5444.4015040
X-RAY DIFFRACTIONr_scangle_it5.5986.4787274
X-RAY DIFFRACTIONr_scangle_other5.5986.4797275
X-RAY DIFFRACTIONr_lrange_it8.95745.79610301
X-RAY DIFFRACTIONr_lrange_other8.95845.80510295
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.59-2.6530.3341230.2823660.28331070.8020.82480.10940.256
2.653-2.720.3271480.24524350.2529830.8280.85586.59070.218
2.72-2.7930.2951400.24224230.24529610.8460.87486.55860.209
2.793-2.8720.2781250.23123250.23428530.8770.87885.87450.2
2.872-2.9580.3161360.22922950.23427930.8530.88287.0390.192
2.958-3.0520.3451530.22922540.23627210.830.87888.46010.193
3.052-3.1560.2561320.20922360.21226340.9080.9189.90130.176
3.156-3.2710.255980.20522180.20725510.9110.91890.78790.177
3.271-3.40.2461070.18720850.1924210.9250.93590.54110.165
3.4-3.5460.2281310.1820730.18323820.9390.94692.52730.164
3.546-3.7120.231020.1819840.18322560.9270.94592.46450.164
3.712-3.9030.287970.1819030.18521620.9170.94492.50690.164
3.903-4.1280.245990.17218540.17520670.9270.94894.48480.155
4.128-4.3970.237900.16217620.16519390.9320.95195.51320.152
4.397-4.7260.2211010.14916440.15318350.9510.96195.09540.14
4.726-5.1420.244660.14515750.14917170.9320.96295.57370.136
5.142-5.6920.224680.16713990.1715450.950.95694.95150.155
5.692-6.4680.262420.18512830.18713940.9240.94495.05020.174
6.468-7.680.281510.18411080.18812240.90.93894.68950.184
7.68-100.237440.1679100.1710210.9410.96493.43780.173

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