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- PDB-3k2h: Co-crystal structure of dihydrofolate reductase/thymidylate synth... -

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Basic information

Entry
Database: PDB / ID: 3k2h
TitleCo-crystal structure of dihydrofolate reductase/thymidylate synthase from Babesia bovis with dUMP, Pemetrexed and NADP
ComponentsDihydrofolate reductase/thymidylate synthase
KeywordsTRANSFERASE / NIAID / SSGCID / Seattle Structural Genomics Center for Infectious Disease / Alimta / folic acid analog / thyA / folate antimetabolites / tic-borne parasitic protozoan / babesiosis / malaria-like disease / Methyltransferase
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/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 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
Chem-LYA / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesBabesia bovis (eukaryote)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsSeattle Structural Genomics Center for Infectious Disease (SSGCID)
CitationJournal: Acta Crystallogr.,Sect.F / Year: 2011
Title: Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis.
Authors: Begley, D.W. / Edwards, T.E. / Raymond, A.C. / Smith, E.R. / Hartley, R.C. / Abendroth, J. / Sankaran, B. / Lorimer, D.D. / Myler, P.J. / Staker, B.L. / Stewart, L.J.
History
DepositionSep 30, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 13, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Refinement description / Version format compliance
Revision 1.2Sep 21, 2011Group: Database references
Revision 1.3Nov 1, 2017Group: Refinement description / Category: software
Revision 1.4Sep 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydrofolate reductase/thymidylate synthase
B: Dihydrofolate reductase/thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,69015
Polymers116,5672
Non-polymers4,12313
Water13,097727
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15330 Å2
ΔGint-28 kcal/mol
Surface area38140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.144, 83.196, 83.378
Angle α, β, γ (deg.)119.690, 90.850, 101.710
Int Tables number1
Space group name H-MP1
DetailsDimeric

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Dihydrofolate reductase/thymidylate synthase


Mass: 58283.656 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Babesia bovis (eukaryote) / Gene: BBOV_II000780 / Production host: Escherichia coli (E. coli) / References: UniProt: A7ASX7, thymidylate synthase

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Non-polymers , 5 types, 740 molecules

#2: Chemical ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP / Deoxyuridine monophosphate


Mass: 308.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical
ChemComp-LYA / 2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC ACID / LY231514 / Pemetrexed


Mass: 427.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H21N5O6 / Comment: medication, chemotherapy*YM
#4: 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
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 727 / 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: 2.56 Å3/Da / Density % sol: 52.05 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 9.5
Details: 11.3 mg/mL BaboA.01191.a, 2 mM dUMP, 2 mM Pemetrexed, NADP carried through from protein purification so it could be NADP or NADPH; soak of apo crystals grown in 20% PEG 8000, 0.1 M CHES pH 9. ...Details: 11.3 mg/mL BaboA.01191.a, 2 mM dUMP, 2 mM Pemetrexed, NADP carried through from protein purification so it could be NADP or NADPH; soak of apo crystals grown in 20% PEG 8000, 0.1 M CHES pH 9.5; crystal tracking ID 204850f1, VAPOR DIFFUSION, SITTING DROP, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Sep 11, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 58064 / % possible obs: 98.5 % / Redundancy: 4 % / Rmerge(I) obs: 0.096 / Χ2: 1.49 / Net I/σ(I): 15.4
Reflection shellResolution: 2.2→2.24 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.286 / Mean I/σ(I) obs: 3.16 / Num. unique all: 2401 / Χ2: 1.036 / % possible all: 82.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 36.51 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å35.56 Å
Translation2.5 Å35.56 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3i3r

3i3r


Resolution: 2.2→35.2 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.921 / WRfactor Rfree: 0.207 / WRfactor Rwork: 0.17 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.818 / SU B: 12.403 / SU ML: 0.143 / SU R Cruickshank DPI: 0.302 / SU Rfree: 0.22 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.302 / ESU R Free: 0.22 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES: RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.239 2917 5.1 %RANDOM
Rwork0.19 ---
obs0.192 57443 97.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 51.29 Å2 / Biso mean: 16.674 Å2 / Biso min: 2.66 Å2
Baniso -1Baniso -2Baniso -3
1-1.4 Å20.6 Å20.21 Å2
2---0.06 Å20.78 Å2
3----0.31 Å2
Refinement stepCycle: LAST / Resolution: 2.2→35.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8001 0 280 727 9008
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0228586
X-RAY DIFFRACTIONr_angle_refined_deg1.5071.99411717
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.55651024
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.68623.452394
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.171151346
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.6041559
X-RAY DIFFRACTIONr_chiral_restr0.1090.21282
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0216599
X-RAY DIFFRACTIONr_mcbond_it0.6541.55067
X-RAY DIFFRACTIONr_mcangle_it1.1728255
X-RAY DIFFRACTIONr_scbond_it1.93333519
X-RAY DIFFRACTIONr_scangle_it2.8514.53451
LS refinement shellResolution: 2.195→2.252 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.263 183 -
Rwork0.201 3389 -
all-3572 -
obs--81.22 %
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)
10.2958-0.2225-0.1280.78420.06890.47280.0122-0.00770.05440.0294-0.02360.0186-0.05670.0230.01140.0141-0.0141-0.00770.02840.00450.047226.8302-16.3551-29.3482
20.2202-0.03860.06840.6857-0.27111.0110.003-0.0455-0.00090.0841-0.045-0.0212-0.02990.02810.0420.0111-0.00670.00250.04270.00950.059136.5256-45.4958-10.8285
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 511
2X-RAY DIFFRACTION1B517
3X-RAY DIFFRACTION2A517

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