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

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Basic information

Entry
Database: PDB / ID: 9dlk
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM1398 ((S)-3-(amino(3-chloro-4-(trifluoromethyl)phenyl)(cyclopropyl)methyl)-6-cyclopropyl-2-methyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one)
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE / inhibitor / Alpha-Beta Barrel / Flavoprotein
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
: / ACETIC ACID / FLAVIN MONONUCLEOTIDE / Chem-OG6 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 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 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.journal_volume ..._audit_author.name / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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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)46,5586
Polymers45,3861
Non-polymers1,1725
Water00
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)85.760, 85.760, 139.507
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Space group name HallP64
Symmetry operation#1: x,y,z
#2: x-y,x,z+2/3
#3: y,-x+y,z+1/3
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z

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Components

#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) / Gene: PFF0160c / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / Strain (production host): DE3
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)
#2: Chemical ChemComp-A1A6D / 3-[(R)-amino[3-chloro-4-(trifluoromethyl)phenyl](cyclopropyl)methyl]-6-cyclopropyl-2-methyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one


Mass: 437.846 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19ClF3N5O / 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-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H4O2
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: 3.26 Å3/Da / Density % sol: 62.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.25 / Details: 1.5 M ammonium sulfate, 0.1 M citric Acid pH 5.25

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: May 7, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
Reflection twinOperator: h,-h-k,-l / Fraction: 0.49
ReflectionResolution: 2.8→50 Å / Num. obs: 14438 / % possible obs: 100 % / Redundancy: 11.3 % / CC1/2: 0.994 / Net I/σ(I): 51.04
Reflection shellResolution: 2.8→2.85 Å / Num. unique obs: 717 / CC1/2: 0.452

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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: 2.9→40.99 Å / Cross valid method: FREE R-VALUE / σ(F): 1.44 / Phase error: 21.4562
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2191 1012 8.17 %
Rwork0.1823 11382 -
obs0.1899 12394 96.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.84 Å2
Refinement stepCycle: LAST / Resolution: 2.9→40.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2923 0 80 0 3003
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00183066
X-RAY DIFFRACTIONf_angle_d0.45984143
X-RAY DIFFRACTIONf_chiral_restr0.041459
X-RAY DIFFRACTIONf_plane_restr0.0033522
X-RAY DIFFRACTIONf_dihedral_angle_d14.47071139
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-3.060.311100.19861234X-RAY DIFFRACTION67.07
3.06-3.250.28771480.18391686X-RAY DIFFRACTION91.73
3.25-3.50.21951480.19331683X-RAY DIFFRACTION91.92
3.5-3.850.21331490.18951683X-RAY DIFFRACTION91.87
3.85-4.410.21321510.17811685X-RAY DIFFRACTION91.78
4.41-5.550.18411440.16851707X-RAY DIFFRACTION92.22
5.55-40.990.21171540.20561712X-RAY DIFFRACTION91.7
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)
11.52447824669-0.4620556965540.1946849296641.360962135740.3973327966411.50519920476-0.1616435953290.1821577790950.113216125740.248727183149-0.2502188010450.4363690741630.153889434513-0.06235616689120.1267401823950.2003586426180.0157286216835-0.01748723976410.182360921568-0.1150096311960.253696175052-18.683072143518.941871483-18.0355101671
20.719385735801-0.705793449765-0.4985016790371.443724906230.9980332719371.70201390989-0.243711903535-0.186808794271-0.3978622658030.515050125996-0.17109863540.3117480642960.748477311945-0.1395399526750.2050201862371.010503501540.0241834164030.1104058923570.3257682468690.01026630336580.307999442253-16.652495114.9520252103-6.25661681518
31.171886522850.327737694938-0.3567392915210.208066922581-0.3158090615850.5020777384340.00820378250714-0.275434580908-0.1450000257720.354057713658-0.1118303352730.4466052671390.053680297775-0.08791418134630.0483278325710.450495567226-0.212737777920.3790339326640.41479546561-0.2341150683650.737411939944-34.778725654513.9254522758-8.95015211844
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 320 )162 - 3201 - 159
22chain 'A' and (resid 321 through 474 )321 - 474160 - 277
33chain 'A' and (resid 475 through 566 )475 - 566278 - 369

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