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- PDB-3o8a: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 3o8a
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with novel Inhibitor Genz667348
ComponentsDihydroorotate dehydrogenase homolog, mitochondrial
KeywordsOXIDOREDUCTASE / alpha beta fold / dihydroorotate dehydrogenase / Pyrimidine biosynthesis / Genz667348 / FAD / Flavoprotein / Mitochondrion inner membrane
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 / Chem-O8A / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsDeng, X. / Booker, M.L. / Phillips, M.A.
CitationJournal: J.Biol.Chem. / Year: 2010
Title: Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model.
Authors: Booker, M.L. / Bastos, C.M. / Kramer, M.L. / Barker, R.H. / Skerlj, R. / Sidhu, A.B. / Deng, X. / Celatka, C. / Cortese, J.F. / Guerrero Bravo, J.E. / Crespo Llado, K.N. / Serrano, A.E. / ...Authors: Booker, M.L. / Bastos, C.M. / Kramer, M.L. / Barker, R.H. / Skerlj, R. / Sidhu, A.B. / Deng, X. / Celatka, C. / Cortese, J.F. / Guerrero Bravo, J.E. / Crespo Llado, K.N. / Serrano, A.E. / Angulo-Barturen, I. / Jimenez-Diaz, M.B. / Viera, S. / Garuti, H. / Wittlin, S. / Papastogiannidis, P. / Lin, J.W. / Janse, C.J. / Khan, S.M. / Duraisingh, M. / Coleman, B. / Goldsmith, E.J. / Phillips, M.A. / Munoz, B. / Wirth, D.F. / Klinger, J.D. / Wiegand, R. / Sybertz, E.
History
DepositionAug 2, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 18, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 23, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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 homolog, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,8765
Polymers46,6521
Non-polymers1,2234
Water64936
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.287, 85.287, 138.719
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Dihydroorotate dehydrogenase homolog, mitochondrial / DHOdehase / Dihydroorotate oxidase


Mass: 46652.344 Da / Num. of mol.: 1 / Fragment: UNP residues 158-383, 414-569
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Strain: 3D7 / Gene: dihydroorotate dehydrogenase, PFF0160c / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 5 types, 40 molecules

#2: Chemical ChemComp-O8A / N-cyclopropyl-5-[2-methyl-5-(trifluoromethoxy)-1H-benzimidazol-1-yl]thiophene-2-carboxamide


Mass: 381.372 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14F3N3O2S
#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: Chemical ChemComp-LDA / LAURYL DIMETHYLAMINE-N-OXIDE / Lauryldimethylamine oxide


Mass: 229.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H31NO / Comment: LDAO, detergent*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 3.12 Å3/Da / Density % sol: 60.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.3
Details: 0.16 M Ammonium sulfate, 0.1 M Sodium Acetate, pH 4.3, 13-15% PEG4000, 25% Glycerol, and 10 mM DTT, 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 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 12, 2009
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: 2.3→50 Å / Num. all: 25531 / Num. obs: 25502 / % possible obs: 98.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.5 % / Rmerge(I) obs: 0.069
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.75 / Mean I/σ(I) obs: 2.6 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.5.0072refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→40 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.951 / SU B: 14.012 / SU ML: 0.154 / Cross valid method: THROUGHOUT / ESU R: 0.246 / ESU R Free: 0.192 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.22935 1297 5.1 %RANDOM
Rwork0.20461 ---
obs0.20593 24110 99.63 %-
all-25531 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 76.572 Å2
Baniso -1Baniso -2Baniso -3
1-1.69 Å20.84 Å20 Å2
2--1.69 Å20 Å2
3----2.53 Å2
Refinement stepCycle: LAST / Resolution: 2.3→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2974 0 84 36 3094
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0223112
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.58124198
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9655374
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.39825.54139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.1715574
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2331511
X-RAY DIFFRACTIONr_chiral_restr0.1160.2465
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212290
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6491.51858
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.2323006
X-RAY DIFFRACTIONr_scbond_it1.89831254
X-RAY DIFFRACTIONr_scangle_it3.0754.51188
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.356 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.296 78 -
Rwork0.306 1783 -
obs--99.31 %
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)
12.49-0.13330.07271.98290.02071.5387-0.23380.2421-0.3330.01270.18250.03680.1538-0.1730.05130.0419-0.05190.0430.1915-0.01490.073222.1402-11.70590.5416
22.21440.48220.38212.5278.80946.2511-0.0539-0.118-0.17450.30390.3241-0.26610.14830.1724-0.27020.11810.04560.07180.16480.09080.137828.597-10.330916.9919
30.5151-1.4697-2.15157.09757.910810.0691-0.24090.06840.01920.3951-0.08890.62990.8249-0.23440.32970.194-0.04660.00910.23260.0570.314618.8692-14.88926.4168
49.64414.4893-1.23513.87834.739515.9551-0.1397-0.05170.2671-0.2780.00180.1897-0.65570.14150.13790.1201-0.06410.0370.12550.01070.069813.4834-13.60937.3255
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A165 - 560
2X-RAY DIFFRACTION2A1001
3X-RAY DIFFRACTION3A1002
4X-RAY DIFFRACTION4A1003

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