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- PDB-4hof: Candida albicans dihydrofolate reductase complexed with NADPH and... -

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Basic information

Entry
Database: PDB / ID: 4hof
TitleCandida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2-methoxy-4-phenylphenyl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine (UCP111H)
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Antifungal Agents / Candida albicans / Drug Design / Enzyme Inhibitors / Fungal Proteins / Structure-Activity Relationship / Tetrahydrofolate Dehydrogenase / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


dihydrofolate metabolic process / glycine biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding / mitochondrion / 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-18H / GLYCINE / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesCandida albicans (yeast)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.76 Å
AuthorsPaulsen, J.L. / Anderson, A.C.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Propargyl-Linked Antifolates are Dual Inhibitors of Candida albicans and Candida glabrata.
Authors: G-Dayanandan, N. / Paulsen, J.L. / Viswanathan, K. / Keshipeddy, S. / Lombardo, M.N. / Zhou, W. / Lamb, K.M. / Sochia, A.E. / Alverson, J.B. / Priestley, N.D. / Wright, D.L. / Anderson, A.C.
History
DepositionOct 22, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 19, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2014Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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
Remark 650HELIX DETERMINATION METHOD: AUTHOR DETERMINED

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydrofolate reductase
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,04011
Polymers44,3892
Non-polymers2,6519
Water6,251347
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,6507
Polymers22,1951
Non-polymers1,4556
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,3904
Polymers22,1951
Non-polymers1,1963
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.931, 66.662, 75.417
Angle α, β, γ (deg.)90.00, 93.13, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Dihydrofolate reductase


Mass: 22194.527 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Candida albicans (yeast) / Gene: DFR1, DHFR / Plasmid: pET41 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P22906, dihydrofolate reductase

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Non-polymers , 5 types, 356 molecules

#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-18H / 5-[3-(2-methoxy-4-phenylphenyl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine / 5-[(3S)-3-(3-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine


Mass: 358.436 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22N4O
#4: Chemical ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 347 / 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: 2.14 Å3/Da / Density % sol: 42.65 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: PEG 3350, KMES, glycine, pH 6.5, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 0.97916 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Jun 26, 2012 / Details: mirrors
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97916 Å / Relative weight: 1
ReflectionResolution: 1.76→50 Å / Num. all: 37060 / Num. obs: 37060 / % possible obs: 99.7 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3 / Redundancy: 4 % / Rmerge(I) obs: 0.07 / Χ2: 3.455 / Net I/σ(I): 18.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.76-1.793.90.20318222.678199.1
1.79-1.8240.17618472.816199.9
1.82-1.8640.15818352.9971100
1.86-1.940.14318833.081199.9
1.9-1.9440.13618073.2681100
1.94-1.9840.12418713.459199.9
1.98-2.0340.11418333.3181100
2.03-2.0940.10618713.4761100
2.09-2.1540.09718343.472199.8
2.15-2.2240.09418743.6211100
2.22-2.340.08618303.6251100
2.3-2.3940.08418623.5651100
2.39-2.540.07918403.6541100
2.5-2.634.10.07418503.5921100
2.63-2.7940.06918943.531100
2.79-3.014.10.06218323.416199.9
3.01-3.314.10.05518793.373199.9
3.31-3.7940.05318723.643199.7
3.79-4.783.90.05518744.159199
4.78-503.50.05518504.504196.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHASERphasing
REFMAC5.6.0117refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1AOE

1aoe


Resolution: 1.76→20.44 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.935 / Occupancy max: 1 / Occupancy min: 0.25 / SU B: 2.264 / SU ML: 0.075 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.136 / ESU R Free: 0.119 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2059 1845 5 %RANDOM
Rwork0.1798 ---
all0.2059 37042 --
obs0.1812 37042 99.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 39.75 Å2 / Biso mean: 15.2527 Å2 / Biso min: 7.5 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.76→20.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3128 0 179 347 3654
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.023399
X-RAY DIFFRACTIONr_angle_refined_deg1.3052.0354624
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8415386
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.18924.085142
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.50615601
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2391522
X-RAY DIFFRACTIONr_chiral_restr0.080.2516
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212487
LS refinement shellResolution: 1.761→1.807 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.223 129 -
Rwork0.208 2444 -
all-2573 -
obs--97.39 %

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