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- PDB-6e0b: Plasmodium falciparum dihydroorotate dehydrogenase C276F mutant b... -

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Basic information

Entry
Database: PDB / ID: 6e0b
TitlePlasmodium falciparum dihydroorotate dehydrogenase C276F mutant bound with triazolopyrimidine-based inhibitor DSM1
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE / PLASMODIUM FALCIPARUM / DIHYDROOROTATE DEHYDROGENASE / TRIAZOLOPYRIMIDINE / INHIBITOR / DSM1 / FAD / FLAVOPROTEIN / MEMBRANE / MITOCHONDRION / MITOCHONDRION INNER MEMBRANE / PYRIMIDINE BIOSYNTHESIS / TRANSIT PEPTIDE
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 ...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-JZ8 / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.099 Å
Model detailsActive enzyme is a monomer.
AuthorsTomchick, D.R. / Phillips, M.A. / Deng, X.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI103947 United States
CitationJournal: ACS Infect Dis / Year: 2019
Title: Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265.
Authors: White, J. / Dhingra, S.K. / Deng, X. / El Mazouni, F. / Lee, M.C.S. / Afanador, G.A. / Lawong, A. / Tomchick, D.R. / Ng, C.L. / Bath, J. / Rathod, P.K. / Fidock, D.A. / Phillips, M.A.
History
DepositionJul 6, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / 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.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 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)46,8258
Polymers45,4301
Non-polymers1,3957
Water2,036113
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2240 Å2
ΔGint2 kcal/mol
Surface area15670 Å2
Unit cell
Length a, b, c (Å)85.522, 85.522, 138.879
Angle α, β, γ (deg.)90.000, 90.000, 120.000
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: 45429.945 Da / Num. of mol.: 1 / Fragment: UNP residues 158-569 with 384-413 deleted / Mutation: C276F
Source method: isolated from a genetically manipulated source
Details: Engineered deletion of residues 1-157 and 384-413
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
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, 120 molecules

#2: Chemical ChemComp-JZ8 / 5-methyl-7-(naphthalen-2-ylamino)-1H-[1,2,4]triazolo[1,5-a]pyrimidine-3,8-diium


Mass: 277.324 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N5
#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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: 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
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 113 / 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: 3.46 Å3/Da / Density % sol: 64.45 % / Mosaicity: 0.377 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.4
Details: 0.06 M ammonium sulfate, 0.1 M sodium acetate, 14% PEG 4000 (w/v), 24% glycerol, 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS3 X 6M / Detector: PIXEL / Date: Jun 14, 2017 / Details: monochromator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.099→50 Å / Num. obs: 33650 / % possible obs: 100 % / Redundancy: 11 % / Biso Wilson estimate: 22.64 Å2 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.016 / Rrim(I) all: 0.053 / Χ2: 0.976 / Net I/σ(I): 10.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.148.31.87716790.470.67920.93100
2.14-2.189.51.48416660.590.5031.5680.948100
2.18-2.2210.11.30116660.6990.4281.370.92100
2.22-2.2610.41.06716850.7810.3451.1220.966100
2.26-2.31100.88716890.8310.2930.9350.963100
2.31-2.3711.20.8116690.890.2520.8490.949100
2.37-2.4211.70.63816610.9370.1940.6670.953100
2.42-2.4911.70.49416890.9570.150.5170.96499.9
2.49-2.5611.60.37216740.9760.1140.3890.98799.9
2.56-2.6511.40.26816710.9890.0830.2810.998100
2.65-2.7411.10.19516930.9920.0610.2041.008100
2.74-2.8510.30.14416880.9940.0470.1521.041100
2.85-2.9811.80.1116740.9960.0330.1151.015100
2.98-3.1411.80.08116820.9970.0250.0851.051100
3.14-3.3311.70.06316800.9980.0190.0661.04199.9
3.33-3.5911.30.05316920.9970.0170.0551.068100
3.59-3.9511.20.04616720.9990.0140.0481.091100
3.95-4.5211.90.04217110.9990.0130.0441.04799.9
4.52-5.7110.03716870.9990.0120.0390.89499.9
5.7-5011.40.0317220.9970.0090.0310.6799.7

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3I65

3i65


Resolution: 2.099→42.761 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 21.73
RfactorNum. reflection% reflection
Rfree0.205 1462 5.04 %
Rwork0.1776 --
obs0.179 28982 86.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 140.5 Å2 / Biso mean: 41.588 Å2 / Biso min: 9.25 Å2
Refinement stepCycle: final / Resolution: 2.099→42.761 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2977 0 169 113 3259
Biso mean--39.27 36.83 -
Num. residues----375
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0994-2.17440.3074270.255253556217
2.1744-2.26150.302880.23581634172252
2.2615-2.36440.26681670.21843013318095
2.3644-2.4890.22781650.209131683333100
2.489-2.64490.2271710.190631853356100
2.6449-2.84910.22241710.182931943365100
2.8491-3.13570.22031640.183131733337100
3.1357-3.58930.18821730.173531943367100
3.5893-4.52130.18171650.153332063371100
4.5213-42.76990.16931710.158732183389100
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)
13.932-1.6841-0.86821.42040.40781.94710.0082-0.2749-0.43870.1709-0.00710.23880.36940.07170.01260.52880.08330.06330.24230.04480.189393.2932-31.83819.8115
20.9516-0.4002-0.31361.30390.49850.59070.00440.0151-0.0510.0583-0.0520.13880.0165-0.04960.06550.32560.14660.03730.1829-0.01680.143692.4893-24.83334.8569
31.1721-0.63330.15051.8432-0.18030.41960.0570.0980.1994-0.1257-0.06440.2866-0.1174-0.1553-0.00490.38970.21740.01650.31410.01710.266586.4228-13.5996-4.3955
47.30514.6671-1.05053.5801-0.64594.7131-0.07290.5090.4274-0.5867-0.06360.0433-0.40420.16160.130.48890.21780.0690.40220.07920.2149101.6531-16.2198-14.1792
51.85940.04570.33131.5966-0.37431.59590.05690.1917-0.0817-0.0178-0.05250.6726-0.1151-0.661-0.01340.27230.10650.00140.4104-0.11530.428775.4909-27.9507-0.7795
61.36451.68811.71764.95133.05247.67890.06110.2539-0.4883-0.2726-0.03210.43070.5952-0.3952-0.04090.41550.0077-0.01690.2766-0.14630.486485.1003-44.1538-3.3738
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 162 through 193 )A162 - 193
2X-RAY DIFFRACTION2chain 'A' and (resid 194 through 299 )A194 - 299
3X-RAY DIFFRACTION3chain 'A' and (resid 300 through 375 )A300 - 375
4X-RAY DIFFRACTION4chain 'A' and (resid 376 through 424 )A376 - 424
5X-RAY DIFFRACTION5chain 'A' and (resid 425 through 534 )A425 - 534
6X-RAY DIFFRACTION6chain 'A' and (resid 535 through 566 )A535 - 566

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