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- PDB-3sfk: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 3sfk
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM267
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / alpha beta fold / pyrimidine biosynthesis / flavoprotein / mitochondrion inner membrane / alpha beta barrel oxidoreductase / inhibitor DSM267 / FMN / Plasmodium falciparum membrane mitochondrion / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


Pyrimidine biosynthesis / pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase activity / 'de novo' UMP biosynthetic process / 'de novo' pyrimidine nucleobase biosynthetic process / mitochondrial inner membrane / plasma membrane
Similarity search - Function
Dihydroorotate dehydrogenase, class 2 / Dihydroorotate dehydrogenase signature 1. / Dihydroorotate dehydrogenase signature 2. / Dihydroorotate dehydrogenase, conserved site / Dihydroorotate dehydrogenase domain / Dihydroorotate dehydrogenase / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-D67 / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsDeng, X. / Phillips, M.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential.
Authors: Coteron, J.M. / Marco, M. / Esquivias, J. / Deng, X. / White, K.L. / White, J. / Koltun, M. / El Mazouni, F. / Kokkonda, S. / Katneni, K. / Bhamidipati, R. / Shackleford, D.M. / Angulo- ...Authors: Coteron, J.M. / Marco, M. / Esquivias, J. / Deng, X. / White, K.L. / White, J. / Koltun, M. / El Mazouni, F. / Kokkonda, S. / Katneni, K. / Bhamidipati, R. / Shackleford, D.M. / Angulo-Barturen, I. / Ferrer, S.B. / Jimenez-Diaz, M.B. / Gamo, F.J. / Goldsmith, E.J. / Charman, W.N. / Bathurst, I. / Floyd, D. / Matthews, D. / Burrows, J.N. / Rathod, P.K. / Charman, S.A. / Phillips, M.A.
History
DepositionJun 13, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 17, 2011Group: Database references
Revision 1.3Jul 26, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.4Sep 13, 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_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2414
Polymers45,2711
Non-polymers9703
Water905
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.586, 86.586, 138.167
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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Components

#1: Protein Dihydroorotate dehydrogenase (quinone), mitochondrial / Dihydroorotate oxidase / DHOdehase


Mass: 45270.820 Da / Num. of mol.: 1 / Fragment: SEE REMARK 999
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PFF0160c / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)
#2: Chemical ChemComp-D67 / 2-(1,1-difluoroethyl)-5-methyl-N-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine


Mass: 357.281 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12F5N5
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#4: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsPROTEIN FRAGMENT COMPRISES UNP RESIDUES 158-383 AND 414-569 WITH RESIDUES 384-413 DELETED.

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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: 3.07 Å3/Da / Density % sol: 59.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.1
Details: 1.64-1.74 M ammonium sulfate, 10 mM DTT, 0.1 M sodium acetate, pH 4.1, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97948
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 21, 2010
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97948 Å / Relative weight: 1
ReflectionResolution: 2.95→50 Å / Num. all: 13217 / Num. obs: 13197 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.5 % / Rmerge(I) obs: 0.1
Reflection shellResolution: 2.95→3 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.755 / Mean I/σ(I) obs: 0.1 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
REFMAC5.5.0072refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3I65

3i65


Resolution: 2.95→50 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.901 / SU B: 36.772 / SU ML: 0.352 / Cross valid method: THROUGHOUT / σ(I): 2 / ESU R: 1.837 / ESU R Free: 0.417 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.286 643 4.9 %RANDOM
Rwork0.224 ---
obs0.227 13197 99.72 %-
all-13217 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 114.766 Å2
Baniso -1Baniso -2Baniso -3
1-0.94 Å20.47 Å20 Å2
2--0.94 Å20 Å2
3----1.4 Å2
Refinement stepCycle: LAST / Resolution: 2.95→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2921 0 67 5 2993
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0223041
X-RAY DIFFRACTIONr_angle_refined_deg1.0571.9964104
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1365366
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.67925.588136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.53115566
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0011510
X-RAY DIFFRACTIONr_chiral_restr0.0620.2456
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022239
X-RAY DIFFRACTIONr_mcbond_it0.2791.51822
X-RAY DIFFRACTIONr_mcangle_it0.51322946
X-RAY DIFFRACTIONr_scbond_it0.48631219
X-RAY DIFFRACTIONr_scangle_it0.8374.51157
LS refinement shellResolution: 2.95→3 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 54 -
Rwork0.295 908 -
obs--100 %
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)
112.7560.4694-2.00041.8463-1.05327.7506-0.10760.0637-0.8287-0.34210.0187-0.13410.40.43790.0890.5572-0.03730.0370.3816-0.09460.5295-11.269-40.113-16.908
26.1282-2.38813.116323.25-0.47643.94550.33660.216-0.8007-0.6550.38020.5486-0.06330.503-0.71680.70260.0190.08480.4644-0.31570.739-1.97-33.904-24.548
37.0084.5911-5.81473.3652-5.08879.7225-0.1880.652-0.4112-0.1180.1567-0.1763-0.24780.15680.03130.60210.18820.02750.5738-0.16530.2792-8.152-25.106-18.583
43.82870.9157-0.88154.91480.9974.6150.2268-0.7936-0.77460.4124-0.3607-0.29250.18580.1760.1340.1516-0.0961-0.02660.21490.15240.2307-8.598-34.0462.181
58.79452.3028-1.67237.9779-1.33046.5491-0.0667-0.5882-0.3588-0.1801-0.1493-0.1513-0.21540.28620.2160.1686-0.06880.05340.1103-0.00760.0771-9.695-26.635-4.096
62.38262.10710.63595.47422.89244.12670.03130.2862-0.2249-0.82590.1101-0.9308-0.72050.5728-0.14130.4678-0.21210.2170.50470.10850.37742.476-18.172-13.985
77.20252.2961-0.16248.0056-0.25713.86460.2655-0.48280.21660.6228-0.4970.5209-0.56950.15590.23150.2555-0.0749-0.02170.1152-0.04010.0607-11.001-21.335-3.236
810.10622.35470.31528.4632-1.04483.2762-0.1772-0.35870.52810.3635-0.0758-0.6329-0.4490.41420.2530.3569-0.2494-0.00250.2244-0.0510.1221-1.527-11.6612.128
919.17316.6238-10.57483.373-4.62210.223-0.49731.0568-0.00850.02920.2376-0.48120.3710.14430.25970.3868-0.1418-0.09050.5638-0.02720.40637.349-11.37810.849
1014.8382-3.2678-5.28760.74571.29464.04040.0058-0.49550.42690.09790.0794-0.0808-0.05290.0495-0.08520.5783-0.07940.0450.5022-0.15210.3889-12.512-10.61916.149
115.59910.93981.47324.41331.59543.582-0.1702-0.9083-0.2020.81690.0051-0.8514-0.2070.74130.16510.4847-0.3541-0.23320.78470.13650.3753.994-20.5749.667
121.6638-3.28762.00346.5591-4.01772.46880.22990.20250.6345-0.7517-0.6587-1.03510.49190.34770.42880.7715-0.07640.34641.5004-0.02661.228816.02-25.286-15.438
132.3131-0.08980.45964.8778-0.20539.84540.2166-0.3082-0.27810.24710.0781-0.71650.40850.2802-0.29470.112-0.0097-0.01770.61070.02640.649913.475-29.5520.898
144.5-1.04561.37627.30110.86853.36960.2614-0.0727-0.74250.3615-0.2184-1.05380.53871.3133-0.04290.31210.0309-0.00930.8080.14780.70363.07-35.016-0.45
159.2934-3.1743-0.60582.97-3.30469.30250.0968-0.6892-0.88480.014-0.18210.10790.93050.7230.08530.44410.0312-0.13730.32920.23140.63171.736-45.8127.011
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A161 - 172
2X-RAY DIFFRACTION2A173 - 177
3X-RAY DIFFRACTION3A178 - 194
4X-RAY DIFFRACTION4A195 - 228
5X-RAY DIFFRACTION5A229 - 247
6X-RAY DIFFRACTION6A248 - 269
7X-RAY DIFFRACTION7A270 - 307
8X-RAY DIFFRACTION8A308 - 347
9X-RAY DIFFRACTION9A355 - 368
10X-RAY DIFFRACTION10A369 - 383
11X-RAY DIFFRACTION11A414 - 458
12X-RAY DIFFRACTION12A459 - 472
13X-RAY DIFFRACTION13A473 - 496
14X-RAY DIFFRACTION14A497 - 542
15X-RAY DIFFRACTION15A543 - 565

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