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

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Basic information

Entry
Database: PDB / ID: 5tbo
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM421
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
Keywordsoxidoreductase/oxidoreductase inhibitor / oxidoreductase / alpha/beta barrel / FMN / mitochondrial membrane / oxidoreductase-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-78Z / 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: 2.151 Å
AuthorsDeng, X. / Phillips, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: ACS Infect Dis / Year: 2016
Title: A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria.
Authors: Phillips, M.A. / White, K.L. / Kokkonda, S. / Deng, X. / White, J. / El Mazouni, F. / Marsh, K. / Tomchick, D.R. / Manjalanagara, K. / Rudra, K.R. / Wirjanata, G. / Noviyanti, R. / Price, R. ...Authors: Phillips, M.A. / White, K.L. / Kokkonda, S. / Deng, X. / White, J. / El Mazouni, F. / Marsh, K. / Tomchick, D.R. / Manjalanagara, K. / Rudra, K.R. / Wirjanata, G. / Noviyanti, R. / Price, R.N. / Marfurt, J. / Shackleford, D.M. / Chiu, F.C. / Campbell, M. / Jimenez-Diaz, M.B. / Bazaga, S.F. / Angulo-Barturen, I. / Martinez, M.S. / Lafuente-Monasterio, M. / Kaminsky, W. / Silue, K. / Zeeman, A.M. / Kocken, C. / Leroy, D. / Blasco, B. / Rossignol, E. / Rueckle, T. / Matthews, D. / Burrows, J.N. / Waterson, D. / Palmer, M.J. / Rathod, P.K. / Charman, S.A.
History
DepositionSep 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 28, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2016Group: Database references
Revision 1.2Dec 21, 2016Group: Database references
Revision 1.3Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 21, 2020Group: Data collection / Category: reflns_shell / Item: _reflns_shell.Rmerge_I_obs
Revision 1.6Oct 4, 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)46,7707
Polymers45,3861
Non-polymers1,3846
Water2,072115
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2270 Å2
ΔGint2 kcal/mol
Surface area15960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.380, 86.380, 138.608
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 (quinone), mitochondrial / DHOdehase / Dihydroorotate oxidase


Mass: 45385.914 Da / Num. of mol.: 1 / Mutation: 384-413 deletion
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)

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Non-polymers , 6 types, 121 molecules

#2: Chemical ChemComp-78Z / 2-(1,1-difluoroethyl)-5-methyl-N-[6-(trifluoromethyl)pyridin-3-yl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine


Mass: 358.269 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H11F5N6
#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: Chemical ChemComp-LDA / LAURYL DIMETHYLAMINE-N-OXIDE


Mass: 229.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H31NO / Comment: LDAO, detergent*YM
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / 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: 3.25 Å3/Da / Density % sol: 59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.4
Details: 0.16 M ammonium sulfate, 0.1 M sodium acetate, pH 4.4, 10% PEG4000, 24% 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 315r / Detector: CCD / Date: Apr 18, 2014
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.15→31.551 Å / Num. obs: 31810 / % possible obs: 99.8 % / Redundancy: 12.4 % / Rmerge(I) obs: 0.052 / Net I/σ(I): 41.1
Reflection shellResolution: 2.15→2.19 Å / Redundancy: 10.2 % / Rmerge(I) obs: 1 / Mean I/σ(I) obs: 1 / CC1/2: 0.565 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASER2.5.6phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3I65

3i65


Resolution: 2.151→31.551 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.31
RfactorNum. reflection% reflection
Rfree0.2191 1343 5.07 %
Rwork0.1809 --
obs0.1828 26502 83.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.151→31.551 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2873 0 95 115 3083
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033011
X-RAY DIFFRACTIONf_angle_d0.7554060
X-RAY DIFFRACTIONf_dihedral_angle_d15.3131139
X-RAY DIFFRACTIONf_chiral_restr0.03448
X-RAY DIFFRACTIONf_plane_restr0.002508
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1514-2.22820.2585380.2685527X-RAY DIFFRACTION18
2.2282-2.31740.3166650.25311262X-RAY DIFFRACTION42
2.3174-2.42290.3021140.25092305X-RAY DIFFRACTION77
2.4229-2.55060.24531440.22953023X-RAY DIFFRACTION99
2.5506-2.71030.26751680.21242985X-RAY DIFFRACTION100
2.7103-2.91940.22851640.20243007X-RAY DIFFRACTION100
2.9194-3.21290.23351690.18363014X-RAY DIFFRACTION100
3.2129-3.67720.21251600.16983002X-RAY DIFFRACTION100
3.6772-4.63060.18771530.14793038X-RAY DIFFRACTION100
4.6306-31.55460.18431680.15522996X-RAY DIFFRACTION98
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)
10.62970.8317-0.36522.4306-0.87081.9526-0.0440.1877-0.0013-0.31420.0863-0.39750.07020.249-0.01530.28540.12970.15720.41330.07790.213323.831-22.6239-19.0488
21.5091-0.9530.45612.5694-0.35220.86230.01620.18150.23010.22290.0135-0.2412-0.30080.03870.09030.2730.15310.0490.20090.08470.206920.4916-17.6193-5.0104
30.9962-0.2855-0.12731.03840.13290.3212-0.0034-0.21210.35780.3376-0.05790.2866-0.397-0.2622-0.05450.53890.35630.2660.2051-0.05270.29719.172-13.3965.1715
42.69060.6853-1.22110.469-0.17342.5841-0.099-0.38770.02150.2613-0.090.23310.144-0.26930.22630.60160.17430.20230.3425-0.02420.22586.482-23.423514.1267
52.1875-0.0801-0.24370.58630.51761.54220.0204-0.1210.78650.19610.0236-0.2166-0.63670.3493-0.0240.8095-0.037-0.02390.1815-0.03810.517625.548-0.85681.5386
64.51490.5421-0.48872.35740.92164.70210.0272-0.30350.52510.42110.0247-0.8005-0.57150.7617-0.10210.3761-0.0468-0.11460.24510.02560.461232.1992-10.64111.2107
75.6865-0.73140.75131.1053-0.97536.0983-0.0356-0.62760.04230.61140.0213-1.00010.08871.278-0.00830.35750.0666-0.22150.52620.04670.621839.309-22.59615.2765
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 162 through 193 )
2X-RAY DIFFRACTION2chain 'A' and (resid 194 through 282 )
3X-RAY DIFFRACTION3chain 'A' and (resid 283 through 376 )
4X-RAY DIFFRACTION4chain 'A' and (resid 377 through 424 )
5X-RAY DIFFRACTION5chain 'A' and (resid 425 through 474 )
6X-RAY DIFFRACTION6chain 'A' and (resid 475 through 537 )
7X-RAY DIFFRACTION7chain 'A' and (resid 538 through 565 )

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