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- PDB-7kyv: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 7kyv
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM634 (3-methyl-N-(1-(5-methylisoxazol-3-yl)ethyl)-4-(4-(trifluoromethyl)benzyl)-1H-pyrrole-2-carboxamide)
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrialDihydroorotate dehydrogenase (quinone)
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Alpha-Beta Barrel / OXIDOREDUCTASE / 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
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-type TIM barrel
Similarity search - Domain/homology
FLAVIN MONONUCLEOTIDE / OROTIC ACID / Chem-XBY / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsDeng, X. / Phillips, M. / Tomchick, D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI103947 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.
Authors: Palmer, M.J. / Deng, X. / Watts, S. / Krilov, G. / Gerasyuto, A. / Kokkonda, S. / El Mazouni, F. / White, J. / White, K.L. / Striepen, J. / Bath, J. / Schindler, K.A. / Yeo, T. / ...Authors: Palmer, M.J. / Deng, X. / Watts, S. / Krilov, G. / Gerasyuto, A. / Kokkonda, S. / El Mazouni, F. / White, J. / White, K.L. / Striepen, J. / Bath, J. / Schindler, K.A. / Yeo, T. / Shackleford, D.M. / Mok, S. / Deni, I. / Lawong, A. / Huang, A. / Chen, G. / Wang, W. / Jayaseelan, J. / Katneni, K. / Patil, R. / Saunders, J. / Shahi, S.P. / Chittimalla, R. / Angulo-Barturen, I. / Jimenez-Diaz, M.B. / Wittlin, S. / Tumwebaze, P.K. / Rosenthal, P.J. / Cooper, R.A. / Aguiar, A.C.C. / Guido, R.V.C. / Pereira, D.B. / Mittal, N. / Winzeler, E.A. / Tomchick, D.R. / Laleu, B. / Burrows, J.N. / Rathod, P.K. / Fidock, D.A. / Charman, S.A. / Phillips, M.A.
History
DepositionDec 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)44,5358
Polymers43,1631
Non-polymers1,3727
Water75742
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.288, 85.288, 139.216
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

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Protein , 1 types, 1 molecules A

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


Mass: 43162.539 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 / Production host: Escherichia coli (E. coli)
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 5 types, 49 molecules

#2: Chemical ChemComp-XBY / 3-methyl-N-[(1R)-1-(5-methyl-1,2-oxazol-3-yl)ethyl]-4-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrrole-2-carboxamide


Mass: 391.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20F3N3O2 / 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 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ORO / OROTIC ACID / Orotic acid


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 42 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.15 Å3/Da / Density % sol: 61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.1
Details: 0.16 M AmSO4, 18% v/v PEG4000, 100 mM Sodium acetate pH 5.1, 24% v/v Glycerol

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: liquid N2 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97943 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97943 Å / Relative weight: 1
ReflectionResolution: 2.4→42.64 Å / Num. obs: 22433 / % possible obs: 100 % / Redundancy: 9.6 % / Biso Wilson estimate: 32.6 Å2 / Rpim(I) all: 0.017 / Net I/σ(I): 46.22
Reflection shellResolution: 2.4→2.44 Å / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1121 / Rpim(I) all: 0.721 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3I65

3i65


Resolution: 2.4→42.64 Å / Cross valid method: FREE R-VALUE / σ(F): 16.82 / Phase error: 22.7417
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1993 1135 6.14 %
Rwork0.1802 17360 -
obs0.1823 18495 82.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.6 Å2
Refinement stepCycle: LAST / Resolution: 2.4→42.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2962 0 94 42 3098
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00663105
X-RAY DIFFRACTIONf_angle_d0.71644183
X-RAY DIFFRACTIONf_chiral_restr0.0428461
X-RAY DIFFRACTIONf_plane_restr0.0043528
X-RAY DIFFRACTIONf_dihedral_angle_d19.4107420
LS refinement shellResolution: 2.4→42.64 Å
RfactorNum. reflection% reflection
Rfree0.186 174 -
Rwork0.1737 2649 -
obs--93.74 %
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)
12.08511445550.7662909112830.9040015119491.08435610670.9261794434061.947898915530.04781847167350.3477775630710.339500120389-0.442249973976-0.002589245811380.211689970839-0.310686034825-0.0419801819498-0.02479449334450.53426790021-0.0590638470312-0.06974029543820.2154376451090.0526578017270.27080431495.0619039832.8366283848-0.42043249466
21.594408464780.7842555370910.1198260711742.461762790040.3508673015850.4602859571160.05701246225550.04022070495630.034107535121-0.153759408226-0.06067303473120.3186584363730.0100440002718-0.134891755630.09662374699250.429063500737-0.156896315614-0.1007072792530.1859229665-0.04130055388490.23535957245188.116151776424.680679876910.3660085447
30.7826191618910.11931824792-0.1610979354222.490686151740.08570626477340.631877102051-0.01384166715330.0214039673342-0.224089360920.025306146441-0.05823262919660.2699802479760.215612325506-0.2299949242810.05046072803150.449883788583-0.285056288477-0.08815788488930.2465196242810.04898527837490.28072810723690.788212974515.322561154816.8359467752
42.03344128491-0.245495170241-0.3973974075381.73974075473-0.49274520841.210458376510.0723923990048-0.3858694265480.01678042275250.263634378164-0.03892278278180.5494032685250.208971084581-0.489710185765-0.0772357865270.374412715235-0.2374900067190.05466519098310.474878911818-0.07842904123980.43370622701479.832812246723.589380452920.9054300092
51.04157611294-0.78670032527-0.3967845223884.724333061392.740981999895.587847529440.050481942485-0.3037376883360.5114300101020.123666361110.00187533513970.279225629601-0.675957402501-0.327884114963-0.06604529659870.41901854041-0.000731212663343-0.04789596224760.309243127624-0.1092670487950.53737874753185.206829392242.716380741216.4521607388
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 356 )
4X-RAY DIFFRACTION4chain 'A' and (resid 357 through 528 )
5X-RAY DIFFRACTION5chain 'A' and (resid 529 through 565 )

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