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- PDB-5boo: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 5boo
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM265
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/INHIBITOR / alpha/beta barrel / redox / dehydrogenase / FMN / inhibitor / mitochondrial membrane / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


Pyrimidine biosynthesis / pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase (quinone) activity / 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 ...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-D65 / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsPhillips, M. / Deng, X. / Tomchick, D.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U01AI075594 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI103947 United States
CitationJournal: Sci Transl Med / Year: 2015
Title: A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.
Authors: Phillips, M.A. / Lotharius, J. / Marsh, K. / White, J. / Dayan, A. / White, K.L. / Njoroge, J.W. / El Mazouni, F. / Lao, Y. / Kokkonda, S. / Tomchick, D.R. / Deng, X. / Laird, T. / Bhatia, S. ...Authors: Phillips, M.A. / Lotharius, J. / Marsh, K. / White, J. / Dayan, A. / White, K.L. / Njoroge, J.W. / El Mazouni, F. / Lao, Y. / Kokkonda, S. / Tomchick, D.R. / Deng, X. / Laird, T. / Bhatia, S.N. / March, S. / Ng, C.L. / Fidock, D.A. / Wittlin, S. / Lafuente-Monasterio, M. / Benito, F.J. / Alonso, L.M. / Martinez, M.S. / Jimenez-Diaz, M.B. / Bazaga, S.F. / Angulo-Barturen, I. / Haselden, J.N. / Louttit, J. / Cui, Y. / Sridhar, A. / Zeeman, A.M. / Kocken, C. / Sauerwein, R. / Dechering, K. / Avery, V.M. / Duffy, S. / Delves, M. / Sinden, R. / Ruecker, A. / Wickham, K.S. / Rochford, R. / Gahagen, J. / Iyer, L. / Riccio, E. / Mirsalis, J. / Bathhurst, I. / Rueckle, T. / Ding, X. / Campo, B. / Leroy, D. / Rogers, M.J. / Rathod, P.K. / Burrows, J.N. / Charman, S.A.
History
DepositionMay 27, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Derived calculations ...Author supporting evidence / Derived calculations / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_audit_support ...entity_src_gen / pdbx_audit_support / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)95,3608
Polymers93,3052
Non-polymers2,0566
Water00
1
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,6804
Polymers46,6521
Non-polymers1,0283
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,6804
Polymers46,6521
Non-polymers1,0283
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.257, 89.257, 275.610
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

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


Mass: 46652.344 Da / Num. of mol.: 2 / Fragment: UNP residues 158-569
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 (E. coli) / Strain (production host): BL21
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)
#2: Chemical ChemComp-D65 / 2-(1,1-difluoroethyl)-5-methyl-N-[4-(pentafluoro-lambda~6~-sulfanyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine / DSM265


Mass: 415.332 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H12F7N5S
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21N4O9P
#4: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H4N2O4

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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: 3.4 Å3/Da / Density % sol: 63.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.8
Details: 16 M ammonium sulfate, 0.1 M Sodium Acetate, pH 4.8, 20% (w/v) PEG4000, 24% (v/v) glycerol, and 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 23, 2010
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.8→44.1 Å / Num. obs: 30850 / % possible obs: 99.8 % / Observed criterion σ(I): 1.1 / Redundancy: 7.5 % / Biso Wilson estimate: 44 Å2 / Rmerge(I) obs: 0.067 / Net I/σ(I): 26.3
Reflection shellResolution: 2.8→2.85 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1 / Mean I/σ(I) obs: 1.1 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data scaling
PHASERphasing
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RX0

4rx0


Resolution: 2.8→44.1 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2536 1987 7.27 %Random
Rwork0.2336 ---
obs0.235 27318 88.71 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.4 Å2
Refinement stepCycle: LAST / Resolution: 2.8→44.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5915 0 138 0 6053
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0046159
X-RAY DIFFRACTIONf_angle_d1.0598329
X-RAY DIFFRACTIONf_dihedral_angle_d15.7412291
X-RAY DIFFRACTIONf_chiral_restr0.039921
X-RAY DIFFRACTIONf_plane_restr0.0041051
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7891-2.85890.2926470.3077587X-RAY DIFFRACTION29
2.8589-2.93610.4013650.3324898X-RAY DIFFRACTION45
2.9361-3.02250.32751110.31771439X-RAY DIFFRACTION70
3.0225-3.120.31341570.30241988X-RAY DIFFRACTION98
3.12-3.23150.28741590.29282044X-RAY DIFFRACTION100
3.2315-3.36090.29811550.28662061X-RAY DIFFRACTION100
3.3609-3.51380.31771640.27642016X-RAY DIFFRACTION100
3.5138-3.69890.28621630.25682055X-RAY DIFFRACTION100
3.6989-3.93050.2521620.23292020X-RAY DIFFRACTION100
3.9305-4.23380.24471620.21732052X-RAY DIFFRACTION100
4.2338-4.65940.20311590.18892041X-RAY DIFFRACTION100
4.6594-5.33270.21451550.19232041X-RAY DIFFRACTION100
5.3327-6.71480.24421680.2192055X-RAY DIFFRACTION100
6.7148-44.06020.19911600.18332034X-RAY DIFFRACTION99
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)
11.4164-0.2408-0.01971.3121-0.06221.6563-0.10260.305-0.4648-0.10860.2932-0.08570.20030.14110.05030.2194-0.0066-0.04550.3641-0.14540.2166-28.8872-4.9544-7.5065
21.42920.04860.53820.4242-0.17750.6833-0.0274-0.20410.020.21220.0528-0.28720.03350.3648-0.17840.2960.0994-0.18520.5162-0.16290.3343-16.74083.31595.8968
31.3120.2684-0.05871.2972-0.25071.4199-0.1842-0.0961-1.04940.24420.1302-0.37640.73880.62290.04350.52390.2135-0.08450.4501-0.03010.8263-19.4809-17.70222.4321
40.55861.2038-1.53483.2761-2.78714.6921-0.0667-0.3354-0.56270.21640.21270.25720.6443-0.2797-0.19750.4523-0.01690.05870.35040.19560.7209-38.4533-18.02337.1375
51.5964-0.0810.22380.70710.12480.7453-0.2069-0.52140.2012-0.05380.23290.1525-0.0852-0.22990.12370.21330.0185-0.12910.47160.02440.274-62.01949.6576-2.6907
61.19220.6297-0.04740.5097-0.0010.2908-0.0682-0.69310.10450.1432-0.06080.3765-0.0657-0.2413-0.12920.41860.22250.00621.56510.01770.5159-73.912810.302913.8902
71.10060.2417-0.06390.72520.47751.4853-0.2402-0.70250.94910.02320.11070.0263-0.4127-0.25610.24390.43870.1711-0.24520.687-0.37680.8822-61.557725.75964.3725
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 162 through 282 )
2X-RAY DIFFRACTION2chain 'A' and (resid 283 through 424 )
3X-RAY DIFFRACTION3chain 'A' and (resid 425 through 535 )
4X-RAY DIFFRACTION4chain 'A' and (resid 536 through 565 )
5X-RAY DIFFRACTION5chain 'B' and (resid 162 through 320 )
6X-RAY DIFFRACTION6chain 'B' and (resid 321 through 448 )
7X-RAY DIFFRACTION7chain 'B' and (resid 449 through 564 )

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