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- PDB-4h95: Candida albicans dihydrofolate reductase complexed with NADPH and... -

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Basic information

Entry
Database: PDB / ID: 4h95
TitleCandida albicans dihydrofolate reductase complexed with NADPH and 6-ethyl-5-{3-[3-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine (UCP1006)
ComponentsDihydrofolate Reductase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Antifungal Agents / Candida albicans / Drug Design / Enzyme Inhibitors / Fungal Proteins / Tetrahydrofolate Dehydrogenase / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


dihydrofolate metabolic process / folic acid metabolic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding / mitochondrion
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-06U / Chem-NDP / Dihydrofolate reductase / Dihydrofolate reductase
Similarity search - Component
Biological speciesCandida albicans (yeast)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.6 Å
AuthorsPaulsen, J.L. / Anderson, A.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Structural analysis of the active sites of dihydrofolate reductase from two species of Candida uncovers ligand-induced conformational changes shared among species.
Authors: Paulsen, J.L. / Viswanathan, K. / Wright, D.L. / Anderson, A.C.
History
DepositionSep 24, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2013Group: Non-polymer description
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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)45,8806
Polymers43,6422
Non-polymers2,2384
Water21612
1
A: Dihydrofolate Reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9403
Polymers21,8211
Non-polymers1,1192
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate Reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9403
Polymers21,8211
Non-polymers1,1192
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)118.482, 118.856, 39.284
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Dihydrofolate Reductase


Mass: 21820.992 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: Q5A5E0, UniProt: P22906*PLUS, dihydrofolate reductase
#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-06U / 6-ethyl-5-{(3R)-3-[3-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine


Mass: 373.451 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23N5O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 3.17 Å3/Da / Density % sol: 61.19 %
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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Nov 11, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.686
11K, H, -L20.314
ReflectionResolution: 2.6→53.02 Å / Num. all: 17769 / Num. obs: 17769 / % possible obs: 99.7 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3 / Redundancy: 6.1 % / Rmerge(I) obs: 0.115 / Χ2: 0.95 / Net I/σ(I): 8.3 / Scaling rejects: 819
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible all
2.6-2.696.310.50731094317251.1399.9
2.69-2.86.290.463.21115817681.0899.9
2.8-2.936.350.4083.71089517101.0699.9
2.93-3.086.320.3264.61128317801.0299.9
3.08-3.286.240.2655.61103717551.0199.7
3.28-3.536.120.2086.91071817370.9499.5
3.53-3.885.820.1658.21038317700.999
3.88-4.455.460.11111.1985417800.8299.4
4.45-5.65.820.08614.41075018250.7599.6
5.6-53.026.260.05821.51216319190.7599.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
d*TREKdata scaling
d*TREK9.9.8.8Ldata reduction
PHASERphasing
REFMAC5.5.0109refinement
PDB_EXTRACT3.11data extraction
StructureStudiodata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1AOE

1aoe


Resolution: 2.6→41.96 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.923 / Occupancy max: 1 / Occupancy min: 0.6 / SU B: 12.013 / SU ML: 0.229 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.108 / ESU R Free: 0.058 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2676 925 5.2 %RANDOM
Rwork0.2404 ---
obs0.2407 17670 98.25 %-
all-17670 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 67.6 Å2 / Biso mean: 53.5495 Å2 / Biso min: 27.74 Å2
Baniso -1Baniso -2Baniso -3
1-1.51 Å20 Å20 Å2
2---4.52 Å20 Å2
3---3.01 Å2
Refinement stepCycle: LAST / Resolution: 2.6→41.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3078 0 152 12 3242
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0223310
X-RAY DIFFRACTIONr_angle_refined_deg0.972.0234508
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9995376
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.67624.085142
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.14615580
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0091522
X-RAY DIFFRACTIONr_chiral_restr0.0610.2502
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212432
X-RAY DIFFRACTIONr_mcbond_it0.2681.51896
X-RAY DIFFRACTIONr_mcangle_it0.49223112
X-RAY DIFFRACTIONr_scbond_it0.46831414
X-RAY DIFFRACTIONr_scangle_it0.8654.51396
LS refinement shellResolution: 2.6→2.658 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.34 60 -
Rwork0.272 1077 -
all-1137 -
obs--87.6 %

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