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- PDB-3ghc: Design, Synthesis, and X-ray Crystal Structure of Classical and N... -

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Entry
Database: PDB / ID: 3ghc
TitleDesign, Synthesis, and X-ray Crystal Structure of Classical and Nonclassical 2-amino-4-oxo-5-substituted-6-thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agenst
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE / protein inhibitor complex folate analogues / NADP / One-carbon metabolism
Function / homology
Function and homology information


regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / response to methotrexate / sequence-specific mRNA binding / 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 / response to methotrexate / sequence-specific mRNA binding / axon regeneration / folic acid binding / dihydrofolate metabolic process / G1/S-Specific Transcription / folic acid metabolic process / dihydrofolate reductase / 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
Chem-GHC / Chem-NDP / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsCody, V.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate ...Title: Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents
Authors: Gangjee, A. / Li, W. / Kisliuk, R.L. / Cody, V. / Pace, J. / Piraino, J. / Makin, J.
History
DepositionMar 3, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,7926
Polymers21,2811
Non-polymers1,5105
Water6,143341
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)84.356, 84.356, 77.767
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Dihydrofolate reductase


Mass: 21281.449 Da / Num. of mol.: 1 / Mutation: Q35S, N64S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHFR, DHFRP1 / Production host: Escherichia coli (E. coli) / Strain (production host): DL3(21) / References: UniProt: P00374, dihydrofolate reductase
#2: Chemical ChemComp-GHC / N-({4-[(2-amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]phenyl}carbonyl)-L-glutamic acid


Type: L-peptide linking / Mass: 476.526 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N4O6S2
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: 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: 2.5 Å3/Da / Density % sol: 50.84 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: 100 mN KPO4, pH 6.9, 30% sat. AmSO4, 3% v/v ethanol, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.9422 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jun 13, 2008 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9422 Å / Relative weight: 1
ReflectionResolution: 1.3→53.22 Å / Num. all: 50745 / Num. obs: 48164 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.3 % / Biso Wilson estimate: 14.6 Å2 / Rmerge(I) obs: 0.045 / Rsym value: 0.022
Reflection shellResolution: 1.3→1.37 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.143 / Mean I/σ(I) obs: 10.3 / Num. unique all: 7389 / Rsym value: 0.075 / % possible all: 99.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.5.0088refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1u72

1u72


Resolution: 1.3→22.51 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.953 / SU B: 0.696 / SU ML: 0.031 / Cross valid method: THROUGHOUT / σ(F): 1 / σ(I): 2 / ESU R: 0.05 / ESU R Free: 0.053 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS, U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1985 2577 5.1 %RANDOM
Rwork0.17003 ---
obs0.17143 48155 99.84 %-
all-50745 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 14.473 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0.01 Å2
Refine analyzeLuzzati coordinate error obs: 0.131 Å
Refinement stepCycle: LAST / Resolution: 1.3→22.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1517 0 95 341 1953
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0320.0221652
X-RAY DIFFRACTIONr_angle_refined_deg2.582.0472246
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3725189
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.7724.50771
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.48315290
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.204159
X-RAY DIFFRACTIONr_chiral_restr0.5510.2236
X-RAY DIFFRACTIONr_gen_planes_refined0.0180.0211233
X-RAY DIFFRACTIONr_mcbond_it1.3461.5941
X-RAY DIFFRACTIONr_mcangle_it2.29121531
X-RAY DIFFRACTIONr_scbond_it3.4323711
X-RAY DIFFRACTIONr_scangle_it5.2534.5715
LS refinement shellResolution: 1.3→1.333 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 179 -
Rwork0.231 3580 -
obs--100 %

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