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

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Basic information

Entry
Database: PDB / ID: 9dky
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM1174 (3-((7-azaspiro[3.5]nonan-7-yl)methyl)-4-cyclopropyl-6-ethyl-2-methyl-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-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
: / FLAVIN MONONUCLEOTIDE / Chem-OG6 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 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 10, 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)46,3554
Polymers45,3861
Non-polymers9693
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)85.303, 85.303, 140.703
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)
References: UniProt: Q08210, dihydroorotate dehydrogenase (quinone)
#2: Chemical ChemComp-A1A59 / 3-[(7-azaspiro[3.5]nonan-7-yl)methyl]-4-cyclopropyl-6-ethyl-2-methyl-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one


Mass: 354.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N4O / 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
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: 62.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 1.8 M Ammonium sulfate, 0.04 M Sodium Acetate pH 4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97935 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 14, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97935 Å / Relative weight: 1
Reflection twinOperator: h,-h-k,-l / Fraction: 0.43
ReflectionResolution: 3.1→50 Å / Num. obs: 10661 / % possible obs: 100 % / Redundancy: 11.3 % / CC1/2: 0.968 / Net I/σ(I): 24.56
Reflection shellResolution: 3.1→3.15 Å / Mean I/σ(I) obs: 1.32 / Num. unique obs: 540 / CC1/2: 0.624

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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: 3.3→46.9 Å / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 29.8832
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2197 803 10.04 %
Rwork0.1777 7194 -
obs0.1861 7997 91.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.96 Å2
Refinement stepCycle: LAST / Resolution: 3.3→46.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2974 0 68 0 3042
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00283098
X-RAY DIFFRACTIONf_angle_d0.56734183
X-RAY DIFFRACTIONf_chiral_restr0.0417462
X-RAY DIFFRACTIONf_plane_restr0.0075527
X-RAY DIFFRACTIONf_dihedral_angle_d13.67791164
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.3-3.510.2629720.1919655X-RAY DIFFRACTION45.36
3.51-3.780.24021410.17661261X-RAY DIFFRACTION87.21
3.78-4.160.21161450.17481320X-RAY DIFFRACTION90.1
4.16-4.760.19121410.16511325X-RAY DIFFRACTION90.32
4.76-5.990.23331410.18091310X-RAY DIFFRACTION90.28
6-46.90.22971580.20181328X-RAY DIFFRACTION89.31
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)
11.067751010050.113154635706-0.4255894553420.485303812499-0.003790118877550.849617791596-0.4243606957930.0915690445298-0.3651192090680.1258753046790.0197516245159-0.2159095005510.2555782099650.0832200683708-0.1803501492670.1212454770020.2284507494960.2118491227380.6595103988640.2274064561990.31136265482126.7359718116-7.180847260677.87583918976
21.01597803203-0.45899761271-0.2744203092570.4769084176310.002808017472320.354539955985-0.09529605735270.368276485783-0.433965708736-0.113827481436-0.08723379448470.3339061953230.18928282896-0.5013984982730.04483979659020.218751497694-0.175568659847-0.01735604110161.08900573426-0.003414416520770.38485379670813.6473720861-7.13345468258-7.6069642001
31.2953246473-0.1757466934920.3588593865190.05222479111510.1083029529281.15668845552-0.1385080954890.512239949865-0.665746326322-0.122545095818-0.0307617020963-0.04071514801270.391737191620.169481548270.3177933245630.5957801543530.03203306545870.5783982261340.604829089735-0.0256751579781.09537323826.0622054724-23.0200631922-0.337523064836
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 161 through 299 )161 - 2991 - 139
22chain 'A' and (resid 300 through 449 )300 - 449140 - 259
33chain 'A' and (resid 450 through 565 )450 - 565260 - 375

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