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- PDB-6vtn: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 6vtn
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM557
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrialDihydroorotate dehydrogenase (quinone)
KeywordsOXIDOREDUCTASE / mitochondria / alpha-beta barrel
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
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
FLAVIN MONONUCLEOTIDE / OROTIC ACID / Chem-RL7 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsDeng, X. / Phillips, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)U01AI075594 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.
Authors: Kokkonda, S. / Deng, X. / White, K.L. / El Mazouni, F. / White, J. / Shackleford, D.M. / Katneni, K. / Chiu, F.C.K. / Barker, H. / McLaren, J. / Crighton, E. / Chen, G. / Angulo-Barturen, I. ...Authors: Kokkonda, S. / Deng, X. / White, K.L. / El Mazouni, F. / White, J. / Shackleford, D.M. / Katneni, K. / Chiu, F.C.K. / Barker, H. / McLaren, J. / Crighton, E. / Chen, G. / Angulo-Barturen, I. / Jimenez-Diaz, M.B. / Ferrer, S. / Huertas-Valentin, L. / Martinez-Martinez, M.S. / Lafuente-Monasterio, M.J. / Chittimalla, R. / Shahi, S.P. / Wittlin, S. / Waterson, D. / Burrows, J.N. / Matthews, D. / Tomchick, D. / Rathod, P.K. / Palmer, M.J. / Charman, S.A. / Phillips, M.A.
History
DepositionFeb 13, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Oct 11, 2023Group: 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: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3394
Polymers45,3861
Non-polymers9533
Water1,29772
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)84.751, 84.751, 137.959
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Space group name HallP64
Symmetry operation#1: x,y,z
#2: x-y,x,z+2/3
#3: y,-x+y,z+1/3
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z

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Components

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


Mass: 45385.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7 / Gene: PFF0160c / Plasmid: pET28b / Production host: Escherichia coli K-12 (bacteria) / Strain (production host): K-12
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)
#2: Chemical ChemComp-RL7 / N-cyclopropyl-4-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-3-methyl-1H-pyrrole-2-carboxamide


Mass: 340.315 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16F4N2O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


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


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


Mass: 18.015 Da / Num. of mol.: 72 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.92 Å3/Da / Density % sol: 63.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.17 M Ammonium Sulfate, 0.1 M Tri-Na citrate, 25% PEG4000, 16% Glycerol, 10 mM DTT
PH range: 5.4-5.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97926 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 2.25→42.38 Å / Num. obs: 26640 / % possible obs: 100 % / Redundancy: 11.3 % / Biso Wilson estimate: 29.44 Å2 / Rpim(I) all: 0.019 / Net I/σ(I): 37.89
Reflection shellResolution: 2.25→2.29 Å / Redundancy: 10.2 % / Mean I/σ(I) obs: 1 / Num. unique obs: 1344 / CC1/2: 0.541 / Rpim(I) all: 0.719 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3I65

3i65


Resolution: 2.25→42.38 Å / Cross valid method: FREE R-VALUE / σ(F): 44.98 / Phase error: 22.5738
RfactorNum. reflection% reflection
Rfree0.2187 1503 7.13 %
Rwork0.2024 --
obs0.2044 21071 79.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 44.57 Å2
Refinement stepCycle: LAST / Resolution: 2.25→42.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2972 0 66 72 3110
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043092
X-RAY DIFFRACTIONf_angle_d0.60914173
X-RAY DIFFRACTIONf_chiral_restr0.0425462
X-RAY DIFFRACTIONf_plane_restr0.003529
X-RAY DIFFRACTIONf_dihedral_angle_d9.13081851
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.330.3031310.2607453X-RAY DIFFRACTION18.86
2.33-2.410.3081520.254711X-RAY DIFFRACTION29.75
2.41-2.510.2365820.23011060X-RAY DIFFRACTION44.09
2.51-2.620.26831240.24141681X-RAY DIFFRACTION70.25
2.62-2.760.24651630.24382204X-RAY DIFFRACTION91.87
2.76-2.930.25531710.23192224X-RAY DIFFRACTION92.86
2.93-3.160.23411700.21872243X-RAY DIFFRACTION92.95
3.16-3.470.22791730.212217X-RAY DIFFRACTION92.76
3.47-3.980.20191690.1852251X-RAY DIFFRACTION93.02
3.98-50.16351700.16372252X-RAY DIFFRACTION92.94
5-27.20.22461770.19532264X-RAY DIFFRACTION92.75
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)
12.09262111446-0.728876425501-1.583475555590.5929685361811.406763678833.35720724075-0.103431510572-0.354383730501-0.456334936160.7155606614870.050651266750.1569568718030.7113303136590.2447425094160.03548666142310.660006984150.1133244290470.0515309058910.3460393386110.03352949025190.29184621171494.3320876871-32.825610624315.9541553959
21.25980575356-0.769948856966-0.4177583446091.982466238660.9302952939781.325049998030.002293689455220.105279560243-0.2010430148160.187087168783-0.1023257444770.2797143687860.127400800028-0.1028480336180.1285959729560.3522632794180.1593774828550.07795389988210.302290464877-0.05875343915730.22179313043287.4449203635-24.68651244125.28327108575
31.50191608316-0.761311249203-0.1814632286681.660466627770.164179852780.3453151397170.07967298107120.2150125048640.0094960029364-0.113934770067-0.2141151121740.180956838226-0.163024117787-0.187097019249-0.0249585052420.356468689660.3114353944970.02909554834250.434994337436-0.01026046832370.21327655820688.6508668134-14.3255378482-3.54424364578
45.24539321722.19835357065-1.36733637822.285119981740.8008645647372.336512757540.1598391855290.6467524330690.266740794182-0.641686123102-0.129693811885-0.194247288995-0.2012199268770.173407143925-0.05334008522930.5327746924270.3007347246270.09981402660590.5770017662870.0802002473360.239254656501100.548522948-16.2052967785-14.3037967173
51.32704256040.874940284446-1.521798675251.66903088143-1.214581492121.785578714880.1178430931240.4003520001680.246375000992-0.271345173510.05758133286130.837346615763-0.0983667976798-0.708550730273-0.1874724935650.4391024791810.2929985432-0.1415682918840.821788545429-0.1832402731390.59217684824271.6037547998-20.3553954167-8.69152493959
63.41770015096-0.470987658609-2.244809113941.338798773680.2835813271975.129770157810.0743409400468-0.0671111865473-0.1948752775390.232477538705-0.04959094760650.687081164099-0.209440669558-0.7115501289310.009064249587150.3834718394340.2126780237870.1317512356570.643080698747-0.141169605320.68138031065172.2879116997-24.03756729377.38821192799
70.903863493838-0.0167665483640.309250076531.83523362491-0.05903206893942.852854879250.11056770360.356614851115-0.49345665725-0.0879901820955-0.1565600475880.7438901539570.167434586085-0.472107727634-8.18896352556E-50.2655531155370.09400402128170.02261541505290.529424697645-0.2304823001710.6150910096577.1771127645-32.8964335486-0.64272615097
80.6988427886310.7994222116050.9605052933814.315109197882.767650296076.92758733110.05607089956880.47155718464-0.799808614775-0.300640935427-0.1078845803610.4770007648990.757193750958-0.1371324459590.01519826932550.4949143238020.04850609897140.01203240091340.512753717315-0.2552481003340.69707616949883.2647102321-44.762803301-5.14141755204
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 162 through 205 )
2X-RAY DIFFRACTION2chain 'A' and (resid 206 through 282 )
3X-RAY DIFFRACTION3chain 'A' and (resid 283 through 375 )
4X-RAY DIFFRACTION4chain 'A' and (resid 376 through 424 )
5X-RAY DIFFRACTION5chain 'A' and (resid 425 through 449 )
6X-RAY DIFFRACTION6chain 'A' and (resid 450 through 474 )
7X-RAY DIFFRACTION7chain 'A' and (resid 475 through 537 )
8X-RAY DIFFRACTION8chain 'A' and (resid 538 through 566 )

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