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- PDB-1e26: Design, Synthesis and X-ray Crystal Structure of a Potent Dual In... -

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Basic information

Entry
Database: PDB / ID: 1.0E+26
TitleDesign, Synthesis and X-ray Crystal Structure of a Potent Dual Inhibitor of Thymidylate Synthase and Dihydrofolate Reductase as an Antitumor Agent.
ComponentsDIHYDROFOLATE REDUCTASE
KeywordsOXIDOREDUCTASE / DIHYDROFOLATE REDUCTASE / THYMIDYLATE SYNTHASE
Function / homology
Function and homology information


glycine biosynthetic process / 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 domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-GPB / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Dihydrofolate reductase
Similarity search - Component
Biological speciesPNEUMOCYSTIS CARINII (fungus)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsGangjee, A. / Yu, J. / McGuire, J.J. / Cody, V. / Galitsky, N. / Kisliuk, R.L. / Queener, S.F.
CitationJournal: Biochemistry / Year: 1999
Title: Ligand-Induced Conformational Changes in the Crystal Structures of Pneumocystis Carinii Dihydrofolate Reductase Complexes with Folate and Nadp+
Authors: Cody, V. / Galitsky, N. / Rak, D. / Luft, J.R. / Pangborn, W. / Queener, S.F.
History
DepositionMay 17, 2000Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 17, 2001Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 23, 2018Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector / _diffrn_detector.type
Revision 1.4May 8, 2019Group: Data collection / Experimental preparation / Category: diffrn_source / exptl_crystal_grow
Item: _diffrn_source.pdbx_synchrotron_y_n / _exptl_crystal_grow.method
Revision 1.5Dec 6, 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 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED. STRANDS 1 TO 7 SHEETS A AND A1 ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DIHYDROFOLATE REDUCTASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0873
Polymers23,9191
Non-polymers1,1692
Water1,820101
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)37.332, 43.231, 61.241
Angle α, β, γ (deg.)90.00, 94.59, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein DIHYDROFOLATE REDUCTASE / / PCDHFR


Mass: 23918.537 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: COMPLEXED WITH NADPH AND INHIBITOR / Source: (gene. exp.) PNEUMOCYSTIS CARINII (fungus) / Gene: C-DNA P.CARINII DHFR / Plasmid: PT7-7 / Gene (production host): C-DNA P.CARINII DHFR / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P16184, dihydrofolate reductase
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-GPB / N-[4-[2-(2-AMINO-4-METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYL]GLUTAMIC ACID


Mass: 425.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23N5O5
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 1.97 Å3/Da / Density % sol: 48 %
Crystal growMethod: microbatch / pH: 6
Details: PROTEIN SOLUTION: WASHED AND CONCENTRATED 4 TUBES PCDHFR USING A CENTRICON 10 50 MM MES, 100MM KCL, B-NADPH, PH 6.0, A280/340 RATIO OF 24. WASHED WITH 50MM MES, 100MM KCL, PH 6.0, WASHED ...Details: PROTEIN SOLUTION: WASHED AND CONCENTRATED 4 TUBES PCDHFR USING A CENTRICON 10 50 MM MES, 100MM KCL, B-NADPH, PH 6.0, A280/340 RATIO OF 24. WASHED WITH 50MM MES, 100MM KCL, PH 6.0, WASHED WITH 50MM MES, 100MM KCL, PH 6.0 TO A CONCENTRATION OF 6.5 MG/ML. RESERVOIR SOLUTION: 50% PEG2000MME, 50MM MES, 100MM, PH 6.0 SET UP MICROBATCH POLYTHERMAL GRADIENT EXPERIMENTS IN MICROPETS. DROPS WERE COMPOSED OF: 2.5 MICROLITERS PROTEIN SOLUTION 2.0 MICROLITERS PROTEIN SOLUTION 0.5 MICROLITERS 50MM MES, 100MM KCL, PH 6.0. MICROPETS WERE LEFT TO EQUILIBRATE ON THE POLYTHERMAL GRADIENT.
Crystal grow
*PLUS
Temperature: 4 ℃ / pH: 6 / Method: unknown
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
19.8 mg/mlprotein11
250 %(w/v)PEG200011
350 mMMES11

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Data collection

DiffractionMean temperature: 293 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200HB / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE / Date: Jan 15, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→100 Å / Num. obs: 11919 / % possible obs: 99.4 % / Observed criterion σ(I): 2 / Redundancy: 2.6 % / Rmerge(I) obs: 0.054
Reflection
*PLUS
Highest resolution: 2 Å / Lowest resolution: 50 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.049
Reflection shell
*PLUS
Highest resolution: 2 Å / Lowest resolution: 2.1 Å / % possible obs: 99.4 %

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Processing

Software
NameClassification
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2CD2

2cd2


Resolution: 2→100 Å / Cross valid method: THROUGHOUT / σ(F): 0
Details: THE C-TERMINAL MET RESIDUE WAS NOT SEEN IN THE DENSITY MAPS
RfactorNum. reflection% reflection
Rfree0.2968 -10 %
Rwork0.2185 --
obs0.2185 13297 -
Refinement stepCycle: LAST / Resolution: 2→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1678 0 79 101 1858
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
Software
*PLUS
Name: CNS_SOLVE / Classification: refinement
Refinement
*PLUS
Lowest resolution: 50 Å / Num. reflection obs: 11919 / Rfactor obs: 0.223 / Rfactor Rfree: 0.297 / Rfactor Rwork: 0.223
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_mcbond_it0.9661.5
X-RAY DIFFRACTIONc_scbond_it0.6942
X-RAY DIFFRACTIONc_mcangle_it1.812
X-RAY DIFFRACTIONc_scangle_it1.2362.5

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