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- PDB-9di6: Crystal structure of Plasmodium falciparum dihydroorotate dehydro... -

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Basic information

Entry
Database: PDB / ID: 9di6
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM679 (ethyl 1,4-dimethyl-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-3-carboxylate)
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/INHIBITOR / inhibitor / Alpha-Beta Barrel / OXIDOREDUCTASE / Flavoprotein / 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-type TIM barrel
Similarity search - Domain/homology
: / CITRIC ACID / FLAVIN MONONUCLEOTIDE / Chem-OG6 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 Å
AuthorsDeng, X. / Tomchick, D. / Phillips, M.
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: 2025
Title: Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.
Authors: Nie, Z. / Bonnert, R. / Tsien, J. / Deng, X. / Higgs, C. / El Mazouni, F. / Zhang, X. / Li, R. / Ho, N. / Feher, V. / Paulsen, J. / Shackleford, D.M. / Katneni, K. / Chen, G. / Ng, A.C.F. / ...Authors: Nie, Z. / Bonnert, R. / Tsien, J. / Deng, X. / Higgs, C. / El Mazouni, F. / Zhang, X. / Li, R. / Ho, N. / Feher, V. / Paulsen, J. / Shackleford, D.M. / Katneni, K. / Chen, G. / Ng, A.C.F. / McInerney, M. / Wang, W. / Saunders, J. / Collins, D. / Yan, D. / Li, P. / Campbell, M. / Patil, R. / Ghoshal, A. / Mondal, P. / Kundu, A. / Chittimalla, R. / Mahadeva, M. / Kokkonda, S. / White, J. / Das, R. / Mukherjee, P. / Angulo-Barturen, I. / Jimenez-Diaz, M.B. / Malmstrom, R. / Lawrenz, M. / Rodriguez-Granillo, A. / Rathod, P.K. / Tomchick, D.R. / Palmer, M.J. / Laleu, B. / Qin, T. / Charman, S.A. / Phillips, M.A.
History
DepositionSep 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jan 29, 2025Group: Structure summary / Category: audit_author / Item: _audit_author.name

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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)46,7496
Polymers45,3861
Non-polymers1,3635
Water64936
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)73.768, 73.768, 328.285
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6

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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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Strain: 3D7 / Gene: PFF0160c / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): DE3
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 6 types, 41 molecules

#2: Chemical ChemComp-A1A51 / ethyl 1,4-dimethyl-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazole-3-carboxylate


Mass: 327.302 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H16F3N3O2 / Feature type: SUBJECT OF INVESTIGATION
#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-OG6 / 6-[bis(oxidanyl)methyl]-5~{H}-pyrimidine-2,4-dione / 6-Formyl-uracil hydrate


Mass: 158.112 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H6N2O4
#5: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#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.: 36 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.84 Å3/Da / Density % sol: 56.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.1
Details: 12% Ethylene Glycol, 0.13M Citric Acid pH 4.1, 9% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97924 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Mar 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97924 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 21869 / % possible obs: 99.9 % / Redundancy: 17.8 % / Biso Wilson estimate: 37.52 Å2 / CC1/2: 0.964 / Net I/σ(I): 35.26
Reflection shellResolution: 2.4→2.44 Å / Redundancy: 16.4 % / Mean I/σ(I) obs: 1.25 / Num. unique obs: 1060 / CC1/2: 0.551 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.41→45.79 Å / SU ML: 0.2486 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.8955
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2483 977 5 %
Rwork0.1954 18547 -
obs0.198 19524 90.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.14 Å2
Refinement stepCycle: LAST / Resolution: 2.41→45.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2914 0 94 36 3044
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00233055
X-RAY DIFFRACTIONf_angle_d0.46924115
X-RAY DIFFRACTIONf_chiral_restr0.0413453
X-RAY DIFFRACTIONf_plane_restr0.0033518
X-RAY DIFFRACTIONf_dihedral_angle_d15.77591144
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.41-2.540.3282580.24671101X-RAY DIFFRACTION38.75
2.54-2.70.30571390.22952641X-RAY DIFFRACTION93.26
2.7-2.90.2771500.21812855X-RAY DIFFRACTION99.93
2.9-3.20.25371530.19642902X-RAY DIFFRACTION100
3.2-3.660.24611520.19212889X-RAY DIFFRACTION100
3.66-4.610.22331570.17292980X-RAY DIFFRACTION100
4.61-45.790.23771680.19673179X-RAY DIFFRACTION99.79
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)
13.651355907541.223441977060.7421292564922.108686328650.7030588324582.3831412921-0.197511703040.06643844123180.241406007178-0.253415232540.153981152602-0.0803000348194-0.3149662767240.002473586530980.02566930449540.236950525428-0.0120627244964-0.04089708260130.1784469487990.05712219919760.213455181828-5.8943499357231.2533498538-7.21050623779
23.797227409070.1973929400450.1234004059453.740810319190.9439355186374.060232362570.0308599478652-0.00534196913662-1.044955511340.2527167947960.0505274084179-0.5857486649950.5371388843130.248551382224-0.08689206190470.250134618572-0.0265891390647-0.05674147195440.2146242729450.02234976289810.528983405089-8.5151874967812.2231766922-8.70786251553
33.03124272399-0.06379769916981.121163850232.322959386131.123303191992.03739513-0.1643810054050.602670084231-0.869482004712-0.3892536549190.352057413469-0.4162541593020.0908934338260.517558049497-0.1391912476570.316539799303-0.04570350066650.04927733353660.477271076474-0.1736610999620.433038001887-1.0324778154415.6752186376-16.6545652083
40.7692795180740.7486506682990.502592458191.010569941030.8039046960391.66138217555-0.4547605671531.309575909480.122564618173-1.018086835920.829789435383-0.667353465116-0.6291821080450.5422932390090.06944372734320.725131725972-0.3827715628730.1081188564570.8084513882230.09723215708530.106224907583-2.3437458125628.7563215524-25.5051986531
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 162 through 297 )162 - 2971 - 136
22chain 'A' and (resid 298 through 376 )298 - 376137 - 214
33chain 'A' and (resid 377 through 474 )377 - 474215 - 277
44chain 'A' and (resid 475 through 565 )475 - 565278 - 368

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