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- PDB-2h2q: Crystal structure of Trypanosoma cruzi Dihydrofolate Reductase-Th... -

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Basic information

Entry
Database: PDB / ID: 2h2q
TitleCrystal structure of Trypanosoma cruzi Dihydrofolate Reductase-Thymidylate synthase
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / TRANSFERASE / Bifunctional enzyme in complex with NADP and dUMP
Function / homology
Function and homology information


thymidylate synthase / thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / mitochondrion / cytosol
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / 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/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / 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 domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
2'-DEOXYURIDINE-5'-MONOPHOSPHATE / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesTrypanosoma cruzi (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsSenkovich, O. / Schormann, N. / Chattopadhyay, D.
CitationJournal: Proteins / Year: 2008
Title: Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi ...Title: Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function.
Authors: Schormann, N. / Senkovich, O. / Walker, K. / Wright, D.L. / Anderson, A.C. / Rosowsky, A. / Ananthan, S. / Shinkre, B. / Velu, S. / Chattopadhyay, D.
History
DepositionMay 19, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Derived calculations / Version format compliance
Revision 1.2Oct 18, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Jul 24, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.location / _software.name / _software.type / _software.version
Revision 1.4Aug 30, 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_ncs_dom_lim / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 999SEQUENCE Authors state that the difference in sequence could arise due to PCR mutation, ...SEQUENCE Authors state that the difference in sequence could arise due to PCR mutation, polymorphism of DHFR-TS or error in database sequence

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,9116
Polymers117,8082
Non-polymers2,1034
Water5,531307
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules

B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,9116
Polymers117,8082
Non-polymers2,1034
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_755-x+2,y,-z+1/21
Buried area6520 Å2
ΔGint-24 kcal/mol
Surface area42130 Å2
MethodPISA
3
A: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,9563
Polymers58,9041
Non-polymers1,0522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
4
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,9563
Polymers58,9041
Non-polymers1,0522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)88.681, 137.250, 189.270
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: 4 / Auth seq-ID: 2 - 515 / Label seq-ID: 2 - 515

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 58904.074 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma cruzi (eukaryote) / Strain: Y / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3)pLysS
References: UniProt: Q27793, dihydrofolate reductase, thymidylate synthase
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-DU / 2'-DEOXYURIDINE-5'-MONOPHOSPHATE / Deoxyuridine monophosphate


Type: DNA linking / Mass: 308.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N2O8P
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 307 / 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: 2.44 Å3/Da / Density % sol: 49.65 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 17% 2-Methyl-2,4-Pentanediol, 10% PEG 4000, 0.1M Potassium citrate, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.9998 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jul 2, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. all: 45396 / Num. obs: 45818 / % possible obs: 99.5 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Rmerge(I) obs: 0.061 / Χ2: 0.628 / Net I/σ(I): 8.2
Reflection shellResolution: 2.4→2.49 Å / Rmerge(I) obs: 0.24 / Num. unique all: 4372 / Χ2: 0.514 / % possible all: 95.8

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019refinement
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT2data extraction
HKL-2000data reduction
CCP4phasing
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1J3I

1j3i


Resolution: 2.4→43.15 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.92 / SU B: 16.021 / SU ML: 0.193 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.541 / ESU R Free: 0.269 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.241 2158 5 %RANDOM
Rwork0.206 ---
obs0.208 43565 95.16 %-
all-45396 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.46 Å2
Baniso -1Baniso -2Baniso -3
1--3.06 Å20 Å20 Å2
2--5.28 Å20 Å2
3----2.22 Å2
Refinement stepCycle: LAST / Resolution: 2.4→43.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8028 0 136 307 8471
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0228368
X-RAY DIFFRACTIONr_angle_refined_deg1.1131.98411375
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2451000
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.66722.774393
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.332151374
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6471581
X-RAY DIFFRACTIONr_chiral_restr0.0670.21235
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026387
X-RAY DIFFRACTIONr_nbd_refined0.1860.23654
X-RAY DIFFRACTIONr_nbtor_refined0.3010.25605
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.2507
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1590.2103
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1030.224
X-RAY DIFFRACTIONr_mcbond_it0.4291.55160
X-RAY DIFFRACTIONr_mcangle_it0.75628095
X-RAY DIFFRACTIONr_scbond_it0.83333659
X-RAY DIFFRACTIONr_scangle_it1.3794.53280
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 3930 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
MEDIUM POSITIONAL0.480.5
MEDIUM THERMAL0.32
LS refinement shellResolution: 2.4→2.452 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.282 116 -
Rwork0.235 2630 -
obs-2746 88.32 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.6394-1.038-0.60321.32181.17132.02290.2170.2109-0.1525-0.1334-0.280.2665-0.2988-0.43020.0630.03730.1591-0.0475-0.109-0.0040.042961.02224.00431.241
22.0537-0.33640.10270.47290.54322.40780.22330.2524-0.5662-0.0215-0.1067-0.00130.0746-0.1966-0.1166-0.03680.01-0.0927-0.202-0.06940.136562.339-13.28933.167
30.4205-0.1188-0.11490.43920.17220.92910.06960.01630.0691-0.086-0.0057-0.0098-0.1937-0.0206-0.06380.10210.00520.0112-0.20870.00230.025994.72517.20820.212
40.48910.0069-0.06110.3664-0.05781.33770.03560.05770.00290.00770.0078-0.00540.1687-0.2177-0.04340.0269-0.042-0.0237-0.15950.01270.023467.805-5.6665.947
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Selection: ALL

IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11AA2 - 2332 - 233
22BB2 - 2332 - 233
33AA234 - 515234 - 515
44BB234 - 515234 - 515

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