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

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Basic information

Entry
Database: PDB / ID: 6lhi
TitleQuadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with C466 (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 / METHIONINE / 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: 2.59 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
DepositionDec 9, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 9, 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)146,9039
Polymers143,8162
Non-polymers3,0867
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11960 Å2
ΔGint-48 kcal/mol
Surface area44720 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

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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
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

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Non-polymers , 5 types, 103 molecules

#2: Chemical ChemComp-MET / METHIONINE


Type: L-peptide linking / Mass: 149.211 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H11NO2S
#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-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: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.606 Å3/Da / Density % sol: 52.8 %
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: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418 Å
DetectorType: Nonius Kappa CCD / Detector: CCD / Date: Oct 9, 2003
RadiationMonochromator: 1.5418 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.59→46.41 Å / Num. obs: 40994 / % possible obs: 90.8 % / Redundancy: 7.874 % / Rmerge(I) obs: 0.071 / Net I/σ(I): 9.8
Reflection shellResolution: 2.59→2.7 Å / Rmerge(I) obs: 0.479 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 4171

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Processing

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

4dp3


Resolution: 2.59→46.41 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.871 / Cross valid method: NONE / ESU R: 0.281 / ESU R Free: 0.087
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.3112 2081 5.076 %
Rwork0.2435 --
all0.247 --
obs-40994 90.138 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 39.668 Å2
Baniso -1Baniso -2Baniso -3
1-12.679 Å20 Å20 Å2
2---14.449 Å2-0 Å2
3---1.77 Å2
Refinement stepCycle: LAST / Resolution: 2.59→46.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8857 0 202 96 9155
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0139280
X-RAY DIFFRACTIONr_bond_other_d0.0340.0178413
X-RAY DIFFRACTIONr_angle_refined_deg1.7191.6612559
X-RAY DIFFRACTIONr_angle_other_deg2.3161.58519579
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.66551055
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.01723.567513
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.357151649
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3581538
X-RAY DIFFRACTIONr_chiral_restr0.0740.21182
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0210099
X-RAY DIFFRACTIONr_gen_planes_other0.0220.021975
X-RAY DIFFRACTIONr_nbd_refined0.2160.21930
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2260.28349
X-RAY DIFFRACTIONr_nbtor_refined0.180.24344
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.23982
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2254
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0460.25
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2250.231
X-RAY DIFFRACTIONr_nbd_other0.2480.272
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.4890.24
X-RAY DIFFRACTIONr_mcbond_it3.8224.1494247
X-RAY DIFFRACTIONr_mcbond_other3.824.1484246
X-RAY DIFFRACTIONr_mcangle_it6.1456.1965293
X-RAY DIFFRACTIONr_mcangle_other6.1446.1975294
X-RAY DIFFRACTIONr_scbond_it3.4674.3745033
X-RAY DIFFRACTIONr_scbond_other3.4674.3745034
X-RAY DIFFRACTIONr_scangle_it5.4326.4467266
X-RAY DIFFRACTIONr_scangle_other5.4336.4467266
X-RAY DIFFRACTIONr_lrange_it8.65746.37910314
X-RAY DIFFRACTIONr_lrange_other8.65746.38210313
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.59-2.6570.5051320.582525X-RAY DIFFRACTION80.175
2.657-2.730.5511590.462628X-RAY DIFFRACTION86.6874
2.73-2.8090.5521420.4372575X-RAY DIFFRACTION86.2266
2.809-2.8960.3661430.4232475X-RAY DIFFRACTION85.9488
2.896-2.990.4741490.3552456X-RAY DIFFRACTION87.8287
2.99-3.0950.4291580.3262411X-RAY DIFFRACTION89.1086
3.095-3.2120.3131250.2642350X-RAY DIFFRACTION90.1968
3.212-3.3430.3111070.2462328X-RAY DIFFRACTION90.7228
3.343-3.4920.2691250.2142254X-RAY DIFFRACTION92.2808
3.492-3.6620.2261260.1922132X-RAY DIFFRACTION92.1257
3.662-3.860.2971090.1912050X-RAY DIFFRACTION92.5815
3.86-4.0940.2681040.1792005X-RAY DIFFRACTION94.1098
4.094-4.3770.232930.1651910X-RAY DIFFRACTION95.4264
4.377-4.7270.2161100.1431763X-RAY DIFFRACTION95.1244
4.727-5.1780.223670.151665X-RAY DIFFRACTION95.585
5.178-5.7880.221770.2011487X-RAY DIFFRACTION94.7879
5.788-6.6820.297380.2131367X-RAY DIFFRACTION95.3836
6.682-8.1810.266560.1831141X-RAY DIFFRACTION94.252
8.181-11.5550.214440.161881X-RAY DIFFRACTION92.5926

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