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- PDB-6de4: Homo sapiens dihydrofolate reductase complexed with beta-NADPH an... -

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Basic information

Entry
Database: PDB / ID: 6de4
TitleHomo sapiens dihydrofolate reductase complexed with beta-NADPH and 3'-[(2R)-4-(2,4-diamino-6-ethylphenyl)but-3-yn-2-yl]-5'-methoxy-[1,1'-biphenyl]-4-carboxylic acid
ComponentsDihydrofolate reductase
Keywordsoxidoreductase/oxidoreductase inhibitor / DHFR / Antifolates / oxidoreductase-oxidoreductase inhibitor complex
Function / homology
Function and homology information


regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / dihydrofolate metabolic process / G1/S-Specific Transcription ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / dihydrofolate metabolic process / G1/S-Specific Transcription / glycine biosynthetic process / dihydrofolate reductase / folic acid metabolic process / dihydrofolate reductase activity / NADPH binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / tetrahydrofolate biosynthetic process / mRNA regulatory element binding translation repressor activity / positive regulation of nitric-oxide synthase activity / one-carbon metabolic process / NADP binding / negative regulation of translation / mRNA 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
ETHANOL / Chem-G6Y / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.411 Å
AuthorsHajian, B. / Wright, D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI104841 United States
CitationJournal: Cell Chem Biol / Year: 2019
Title: Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.
Authors: Hajian, B. / Scocchera, E. / Shoen, C. / Krucinska, J. / Viswanathan, K. / G-Dayanandan, N. / Erlandsen, H. / Estrada, A. / Mikusova, K. / Kordulakova, J. / Cynamon, M. / Wright, D.
History
DepositionMay 11, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 23, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)45,73418
Polymers42,6992
Non-polymers3,03516
Water1,26170
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,8238
Polymers21,3501
Non-polymers1,4747
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,91110
Polymers21,3501
Non-polymers1,5629
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)104.611, 104.660, 144.333
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-322-

HOH

21A-328-

HOH

31B-316-

HOH

41B-323-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Dihydrofolate reductase /


Mass: 21349.525 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHFR / Production host: Escherichia coli (E. coli) / References: UniProt: P00374, dihydrofolate reductase

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Non-polymers , 8 types, 86 molecules

#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-G6Y / 3'-[(2R)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-5'-methoxy[1,1'-biphenyl]-4-carboxylic acid


Mass: 416.472 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H24N4O3
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-EOH / ETHANOL / Ethanol


Mass: 46.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O
#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 70 / 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: 4.63 Å3/Da / Density % sol: 73.41 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.1M Tris Ph 7.6,0.2M LiSo4, 15mM CaCl2, 6% EtOH, 15% Ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.411→42.364 Å / Num. obs: 30735 / % possible obs: 99.45 % / Redundancy: 7.7 % / Rpim(I) all: 0.082 / Rsym value: 0.082 / Net I/σ(I): 7.4
Reflection shellResolution: 2.41→2.45 Å / Rpim(I) all: 0.779 / Rsym value: 0.779

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4KAK

4kak


Resolution: 2.411→42.364 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 21.99
RfactorNum. reflection% reflection
Rfree0.2205 1987 6.46 %
Rwork0.1812 --
obs0.1837 30735 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.411→42.364 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3004 0 196 70 3270
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083395
X-RAY DIFFRACTIONf_angle_d1.0574620
X-RAY DIFFRACTIONf_dihedral_angle_d16.3521310
X-RAY DIFFRACTIONf_chiral_restr0.041477
X-RAY DIFFRACTIONf_plane_restr0.004593
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4107-2.4710.25221340.21541927X-RAY DIFFRACTION95
2.471-2.53780.25731400.21632027X-RAY DIFFRACTION100
2.5378-2.61240.25881430.21362023X-RAY DIFFRACTION100
2.6124-2.69680.24571410.19852038X-RAY DIFFRACTION100
2.6968-2.79310.24651440.19212040X-RAY DIFFRACTION100
2.7931-2.90490.21761460.18882044X-RAY DIFFRACTION100
2.9049-3.03710.25981390.19922030X-RAY DIFFRACTION100
3.0371-3.19720.21861380.21992075X-RAY DIFFRACTION100
3.1972-3.39740.24681360.20122047X-RAY DIFFRACTION100
3.3974-3.65960.23781430.17132072X-RAY DIFFRACTION100
3.6596-4.02760.21231430.16852070X-RAY DIFFRACTION100
4.0276-4.60980.19351420.14262082X-RAY DIFFRACTION100
4.6098-5.80550.16381450.16342102X-RAY DIFFRACTION100
5.8055-42.37080.24761530.19972171X-RAY DIFFRACTION99

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