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- PDB-3dg8: Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum di... -

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Basic information

Entry
Database: PDB / ID: 3dg8
TitleQuadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with RJF670, NADPH, and dUMP
Components(Bifunctional dihydrofolate reductase-thymidylate ...) x 2
KeywordsOXIDOREDUCTASE / TRANSFERASE / Alpha-Beta / Methyltransferase
Function / homology
Function and homology information


Interconversion of nucleotide di- and triphosphates / thymidylate synthase / thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / nucleotide binding ...Interconversion of nucleotide di- and triphosphates / thymidylate synthase / thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / nucleotide binding / mitochondrion / RNA binding / cytoplasm / cytosol
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / 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 ...Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / 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 / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-NDP / Chem-RJ6 / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.58 Å
AuthorsDasgupta, T. / Chitnumsub, P. / Maneeruttanarungroj, C. / Kamchonwongpaisan, S. / Nichols, S. / Lyons, T.M. / Tirado-Rives, J. / Jorgensen, W.L. / Yuthavong, Y. / Anderson, K.S.
CitationJournal: Acs Chem.Biol. / Year: 2009
Title: Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria.
Authors: Dasgupta, T. / Chitnumsub, P. / Kamchonwongpaisan, S. / Maneeruttanarungroj, C. / Nichols, S.E. / Lyons, T.M. / Tirado-Rives, J. / Jorgensen, W.L. / Yuthavong, Y. / Anderson, K.S.
History
DepositionJun 13, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 27, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,43410
Polymers143,8534
Non-polymers2,5826
Water4,684260
1
A: Bifunctional dihydrofolate reductase-thymidylate synthase
C: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,2175
Polymers71,9262
Non-polymers1,2913
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1820 Å2
ΔGint-8.4 kcal/mol
Surface area28690 Å2
MethodPISA
2
B: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,2175
Polymers71,9262
Non-polymers1,2913
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint-8.5 kcal/mol
Surface area28900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.516, 155.404, 165.183
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsThe biological unit is the same as asymmetric unit.

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Components

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Bifunctional dihydrofolate reductase-thymidylate ... , 2 types, 4 molecules ABCD

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 33213.309 Da / Num. of mol.: 2 / Fragment: Residues 1-280 / Mutation: N51I, C59R, S108N, I164L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Strain: V1/S / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q8I1R6, UniProt: P13922*PLUS, dihydrofolate reductase, thymidylate synthase
#2: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 38712.949 Da / Num. of mol.: 2 / Fragment: Residues 281-608
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Strain: V1/S / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q8I1R6, UniProt: P13922*PLUS, dihydrofolate reductase, thymidylate synthase

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Non-polymers , 4 types, 266 molecules

#3: Chemical ChemComp-RJ6 / N-(3,5-dimethoxyphenyl)imidodicarbonimidic diamide / {[(3,5-dimethoxyanilino)(imino)methyl]amino}methanimidamide


Mass: 237.258 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O2
#4: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#5: Chemical ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N2O8P
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 260 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsTHE SEQUENCE INFORMATION PROVIDED BY AUTHORS IS THE GENBANK ENTRY ABU43156.1

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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: 2.52 Å3/Da / Density % sol: 50.8 %
Crystal growTemperature: 297 K / pH: 4.6
Details: PEG 4000, NH4OAc, pH 4.6, MICROBATCH, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1 / Wavelength: 1
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 10, 2007 / Details: MIRRORS
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.56→50 Å / Num. obs: 45609 / % possible obs: 97.6 % / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Biso Wilson estimate: 39.4 Å2 / Rmerge(I) obs: 0.066 / Net I/σ(I): 16.5
Reflection shellResolution: 2.56→2.65 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.265 / Mean I/σ(I) obs: 6.36 / Rsym value: 0.265 / % possible all: 95

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.006data extraction
HKL-2000data reduction
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1J3K

1j3k


Resolution: 2.58→49.43 Å / Occupancy max: 1 / Occupancy min: 1 / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.239 2321 5 %RANDOM
Rwork0.199 ---
obs0.199 45609 97.6 %-
all-45609 --
Solvent computationBsol: 36.44 Å2
Displacement parametersBiso mean: 46.26 Å2
Baniso -1Baniso -2Baniso -3
1-9.23 Å20 Å20 Å2
2---2.129 Å20 Å2
3----7.102 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.34 Å0.29 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 2.58→49.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9101 0 170 260 9531
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.24
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.19
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1CNS_TOPPAR:PROTEIN_REP.PARAM
X-RAY DIFFRACTION2LIGANDS_1.PARAM
X-RAY DIFFRACTION3CNS_TOPPAR:WATER_REP.PARAM

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