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- PDB-5t7o: Crystal structure of Trypanosoma cruzi Dihydrofolate Reductase-Th... -

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Entry
Database: PDB / ID: 5t7o
TitleCrystal structure of Trypanosoma cruzi Dihydrofolate Reductase-Thymidylate Synthase in complex with (6S)-5,6,7,8-TETRAHYDROFOLATE
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / transferase / folate metabolism / trypanosomatidic infections / trypanosoma cruzi
Function / homology
Function and homology information


thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / nucleotide binding
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase ...Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / (6S)-5,6,7,8-TETRAHYDROFOLATE / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesTrypanosoma cruzi (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDi Pisa, F. / Dello Iacono, L. / Bonucci, A. / Mangani, S.
Funding support Italy, 1items
OrganizationGrant numberCountry
European Union603240 Italy
CitationJournal: To Be Published
Title: Crystal structure of Trypanosoma cruzi Dihydrofolate Reductase-Thymidylate Synthase in complex with (6S)-5,6,7,8-TETRAHYDROFOLATE
Authors: Di Pisa, F. / Dello Iacono, L. / Bonucci, A. / Mangani, S.
History
DepositionSep 5, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 20, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.2Jan 17, 2024Group: 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: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)244,61863
Polymers235,7124
Non-polymers8,90559
Water36,4622024
1
A: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,46434
Polymers117,8562
Non-polymers4,60832
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14110 Å2
ΔGint48 kcal/mol
Surface area39800 Å2
MethodPISA
2
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,15429
Polymers117,8562
Non-polymers4,29727
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14110 Å2
ΔGint53 kcal/mol
Surface area38940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)154.547, 173.540, 174.159
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11D-1079-

HOH

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 58928.121 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma cruzi (strain CL Brener) (eukaryote)
Strain: CL Brener / Gene: Tc00.1047053509153.90 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q4DLS1

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Non-polymers , 5 types, 2083 molecules

#2: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical
ChemComp-THG / (6S)-5,6,7,8-TETRAHYDROFOLATE


Mass: 445.429 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H23N7O6
#4: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H13N2O8P
#5: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 47 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2024 / 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: 2.63 Å3/Da / Density % sol: 53.19 %
Crystal growTemperature: 298 K / Method: microbatch
Details: TcDHFR-TS 12.5 mg ml-1 in 25 mMTris pH 7.2 and 80 mMNaCl, precipitant solution 12% (w/v) PEG 3350, 100 mM sodium malonate pH 5
PH range: 5.5-7-5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96861 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 7, 2015
RadiationMonochromator: Si111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 1.8→86.77 Å / Num. obs: 213627 / % possible obs: 99.5 % / Observed criterion σ(I): 2 / Redundancy: 6.5 % / Net I/σ(I): 9.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
iMOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3INV

3inv


Resolution: 1.8→86.77 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.953 / SU B: 2.77 / SU ML: 0.086 / Cross valid method: THROUGHOUT / ESU R: 0.124 / ESU R Free: 0.122
RfactorNum. reflection% reflectionSelection details
Rfree0.21991 10547 4.9 %RANDOM
Rwork0.1769 ---
obs0.17906 202617 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 26.495 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2---0.01 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.8→86.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15441 0 588 2024 18053
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0260.01917033
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.3921.98923157
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.48152114
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.03222.651762
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.54152703
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.54515158
X-RAY DIFFRACTIONr_chiral_restr0.2020.22536
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.02112893
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.7482.2928066
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.6443.40610090
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.8282.6868964
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined7.97421.44328502
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.288 739 -
Rwork0.241 14882 -
obs--98.9 %

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