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

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Basic information

Entry
Database: PDB / ID: 4hoe
TitleCandida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2,5-dimethoxy-4-phenylphenyl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine (UCP111E)
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 reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding
Similarity search - Function
Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase / 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-18G / GLYCINE / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesCandida albicans (yeast)
MethodX-RAY DIFFRACTION / SYNCHROTRON / 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 1.2Sep 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)46,9169
Polymers44,3892
Non-polymers2,5277
Water6,143341
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,4965
Polymers22,1951
Non-polymers1,3014
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,4214
Polymers22,1951
Non-polymers1,2263
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.003, 66.538, 75.795
Angle α, β, γ (deg.)90.00, 93.11, 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, 348 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-18G / 5-[3-(2,5-dimethoxy-4-phenylphenyl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine / 5-[(3S)-3-(2,5-dimethoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine


Mass: 388.462 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N4O2
#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.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 341 / 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: 2.16 Å3/Da / Density % sol: 42.94 %
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: 37088 / Num. obs: 37088 / % possible obs: 98.1 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3 / Redundancy: 3.7 % / Rmerge(I) obs: 0.063 / Χ2: 3.373 / Net I/σ(I): 18.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.76-1.793.60.20216502.309187.4
1.79-1.823.90.17818662.42198.7
1.82-1.863.90.16418372.486199.8
1.86-1.93.80.14419062.695199.7
1.9-1.943.80.13318582.907198.9
1.94-1.983.80.12318663.027199.6
1.98-2.033.80.11418593.167199
2.03-2.093.80.10818693.421199.7
2.09-2.153.70.118763.498199.3
2.15-2.223.80.09118743.612199.4
2.22-2.33.70.08518643.712199.1
2.3-2.393.70.08218893.724199.2
2.39-2.53.70.07618153.793199.1
2.5-2.633.60.07118843.935199.1
2.63-2.793.60.06518794199.2
2.79-3.013.60.05718703.816198.3
3.01-3.313.40.04918723.675198.2
3.31-3.793.40.04318443.635197
3.79-4.783.30.03918593.607196.9
4.78-503.50.04818514.233195.6

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Processing

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

1aoe


Resolution: 1.76→20.5 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.938 / Occupancy max: 1 / Occupancy min: 0.4 / SU B: 2.284 / SU ML: 0.075 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.137 / ESU R Free: 0.125 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.216 1853 5 %RANDOM
Rwork0.1815 ---
all0.216 37070 --
obs0.1832 37070 98.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 43.65 Å2 / Biso mean: 16.9376 Å2 / Biso min: 7.99 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.76→20.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3128 0 171 341 3640
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0193384
X-RAY DIFFRACTIONr_angle_refined_deg1.2722.0064604
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9985384
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.84124.126143
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.52615601
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6071522
X-RAY DIFFRACTIONr_chiral_restr0.0780.2511
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212654
LS refinement shellResolution: 1.76→1.803 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.246 141 -
Rwork0.207 2491 -
all-2632 -
obs--95.85 %

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