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

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Basic information

Entry
Database: PDB / ID: 6lez
TitleQuadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with compound 46 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-EA0 / Chem-NDP / PHOSPHATE ION / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.644 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)146,1478
Polymers143,8162
Non-polymers2,3306
Water1,06359
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11100 Å2
ΔGint-54 kcal/mol
Surface area44840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.703, 155.878, 164.800
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 / 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 (E. coli) / References: UniProt: D9N170
#2: Chemical ChemComp-EA0 / 2-[[4,6-bis(azanyl)-2,2-dimethyl-1,3,5-triazin-1-yl]oxy]-N-(4-chlorophenyl)ethanamide


Mass: 324.766 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H17ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / 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: 2.77 Å3/Da / Density % sol: 55.64 %
Crystal growTemperature: 298 K / Method: microbatch / pH: 4.6
Details: 0.1 mM sodium acetate, pH 4.6, 0.2 M 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
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.64→10 Å / Num. obs: 45387 / % possible obs: 90.6 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.103 / Net I/σ(I): 10.8
Reflection shellResolution: 2.64→2.69 Å / Rmerge(I) obs: 0.445 / Num. unique obs: 6232

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Processing

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

4dp3


Resolution: 2.644→10 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.897 / SU B: 13.155 / SU ML: 0.27 / Cross valid method: NONE / ESU R: 1.394 / ESU R Free: 0.374
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2714 1915 4.908 %
Rwork0.1876 --
all0.192 --
obs-39019 87.813 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 50.938 Å2
Baniso -1Baniso -2Baniso -3
1-3.883 Å20 Å20 Å2
2---0.891 Å20 Å2
3----2.992 Å2
Refinement stepCycle: LAST / Resolution: 2.644→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8747 0 150 59 8956
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0139111
X-RAY DIFFRACTIONr_bond_other_d0.0020.0178268
X-RAY DIFFRACTIONr_angle_refined_deg1.7181.66612333
X-RAY DIFFRACTIONr_angle_other_deg1.2151.59619224
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.47851040
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.81623.598503
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.414151614
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4351538
X-RAY DIFFRACTIONr_chiral_restr0.1040.21170
X-RAY DIFFRACTIONr_chiral_restr_other0.9520.212
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.029928
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021956
X-RAY DIFFRACTIONr_nbd_refined0.2120.21804
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1870.28257
X-RAY DIFFRACTIONr_nbtor_refined0.1760.24285
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.24129
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1790.2231
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0820.23
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2460.222
X-RAY DIFFRACTIONr_nbd_other0.2690.235
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1130.26
X-RAY DIFFRACTIONr_mcbond_it4.5955.2864190
X-RAY DIFFRACTIONr_mcbond_other4.5945.2854189
X-RAY DIFFRACTIONr_mcangle_it7.1847.8955220
X-RAY DIFFRACTIONr_mcangle_other7.1837.8965221
X-RAY DIFFRACTIONr_scbond_it4.3915.6524921
X-RAY DIFFRACTIONr_scbond_other4.3875.654915
X-RAY DIFFRACTIONr_scangle_it6.8498.3267113
X-RAY DIFFRACTIONr_scangle_other6.8488.3287107
X-RAY DIFFRACTIONr_lrange_it9.77559.09110081
X-RAY DIFFRACTIONr_lrange_other9.77859.09710080
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
2.644-2.7080.391110.30823100.31230010.7070.74780.67310.28
2.708-2.7760.3651060.27923680.28229380.7870.81584.20690.245
2.776-2.850.3491160.25723670.26128670.8140.85286.60620.22
2.85-2.9310.3031450.23922870.24327830.8580.87387.38770.201
2.931-3.0180.3651380.2422880.24627400.8210.87788.54010.203
3.018-3.1140.3431100.23322100.23826280.8390.87888.28010.201
3.114-3.2190.2761270.20721460.21125780.8860.9188.16910.176
3.219-3.3370.2631050.19320980.19624630.9120.92789.44380.166
3.337-3.4670.2731040.19720150.20123950.9070.92888.4760.177
3.467-3.6150.2621240.19519120.19923160.9060.92887.91020.18
3.615-3.7830.266960.19318600.19722030.9160.93288.7880.18
3.783-3.9770.245760.17518060.17821090.9190.9489.23660.167
3.977-4.2050.272690.1718170.17420170.9110.94893.50520.163
4.205-4.4760.21980.13717670.14119030.9470.96498.00320.135
4.476-4.8080.254720.14216590.14617840.940.96297.02920.141
4.808-5.2260.215700.14615490.14916580.9520.96197.64780.145
5.226-5.7780.26720.16914170.17415350.9320.94897.00330.166
5.778-6.5510.311690.19512540.20113610.9040.93197.20790.19
6.551-7.7490.27540.17611010.1812090.9210.94895.53350.177
7.749-100.214530.1588740.1619980.960.9792.88580.169

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