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- PDB-6nd2: Staphylococcus aureus Dihydrofolate Reductase complexed with NADP... -

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Basic information

Entry
Database: PDB / ID: 6nd2
TitleStaphylococcus aureus Dihydrofolate Reductase complexed with NADPH and 6-ETHYL-5-[(3R)-3-[2-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL]PYRIMIDINE-2,4-DIAMINE (UCP1063)
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE / DHFR / Propargyl-linked antifolates / antibiotics / antifolates
Function / homology
Function and homology information


dihydrofolate metabolic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding / cytosol
Similarity search - Function
Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-G8J / Tricyclic NADPH / Dihydrofolate reductase
Similarity search - Component
Biological speciesStaphylococcus aureus (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.243 Å
AuthorsReeve, S.M. / Wright, D.L.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI104841 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI111957 United States
CitationJournal: Drug Metab.Dispos. / Year: 2019
Title: Structure-Guided In Vitro to In Vivo Pharmacokinetic Optimization of Propargyl-Linked Antifolates.
Authors: Lombardo, M.N. / G-Dayanandan, N. / Keshipeddy, S. / Zhou, W. / Si, D. / Reeve, S.M. / Alverson, J. / Barney, P. / Walker, L. / Hoody, J. / Priestley, N.D. / Obach, R.S. / Wright, D.L.
History
DepositionDec 13, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
X: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,2274
Polymers18,0161
Non-polymers1,2113
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.878, 78.878, 107.908
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Dihydrofolate reductase / DHFR


Mass: 18015.557 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Staphylococcus aureus (bacteria) / Gene: folA / Plasmid: pET41a+ / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0A017, dihydrofolate reductase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-G8J / 6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine


Mass: 373.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23N5O
#4: Chemical ChemComp-XNP / Tricyclic NADPH


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / Source method: isolated from a natural source / Formula: H2O

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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: 2.69 Å3/Da / Density % sol: 54.27 %
Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1M MES, pH 5.0, 0.1M Sodium Acetate, 13% PEG 10K, 20% gamma-butrylactone

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Nov 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.24→50 Å / Num. obs: 9714 / % possible obs: 96.82 % / Redundancy: 15.8 % / Rmerge(I) obs: 0.148 / Net I/σ(I): 16.06
Reflection shellResolution: 2.24→2.28 Å / Redundancy: 11.6 % / Rmerge(I) obs: 0.623 / Mean I/σ(I) obs: 1.7

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3F0Q

3f0q


Resolution: 2.243→39.439 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.27
RfactorNum. reflection% reflection
Rfree0.2352 970 9.99 %
Rwork0.1846 --
obs0.1896 9714 96.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.243→39.439 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1273 0 82 37 1392
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0121407
X-RAY DIFFRACTIONf_angle_d1.7461922
X-RAY DIFFRACTIONf_dihedral_angle_d10.0681188
X-RAY DIFFRACTIONf_chiral_restr0.151215
X-RAY DIFFRACTIONf_plane_restr0.008235
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2428-2.3610.32791140.23191030X-RAY DIFFRACTION83
2.361-2.50890.26411310.22491187X-RAY DIFFRACTION95
2.5089-2.70260.29611390.22791253X-RAY DIFFRACTION100
2.7026-2.97450.30941420.21931275X-RAY DIFFRACTION100
2.9745-3.40470.25041440.20031288X-RAY DIFFRACTION100
3.4047-4.28870.21391440.15851298X-RAY DIFFRACTION100
4.2887-39.44510.17761560.15681413X-RAY DIFFRACTION100

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