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

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Basic information

Entry
Database: PDB / ID: 9diz
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM959 (6-cyclopropyl-2,4-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one)
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
: / FLAVIN MONONUCLEOTIDE / Chem-OG6 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 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
Citation
Journal: 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.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionSep 6, 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)46,3634
Polymers45,3861
Non-polymers9773
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)85.224, 85.224, 139.888
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-A1A53 / 6-cyclopropyl-2,4-dimethyl-3-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one


Mass: 362.349 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17F3N4O / 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: 3.23 Å3/Da / Density % sol: 61.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 1.6 M Ammonium sulfate, 0.1 M Citric Acid pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97918 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Feb 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
Reflection twinOperator: h,-h-k,-l / Fraction: 0.38
ReflectionResolution: 2.9→50 Å / Num. obs: 12638 / % possible obs: 99 % / Redundancy: 10.3 % / CC1/2: 0.97 / Net I/σ(I): 10.06
Reflection shellResolution: 2.9→2.95 Å / Mean I/σ(I) obs: 1.01 / Num. unique obs: 613 / CC1/2: 0.463

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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: 3.1→40.76 Å / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.0913
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2283 955 10.25 %
Rwork0.1936 8365 -
obs0.1976 9320 88.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.59 Å2
Refinement stepCycle: LAST / Resolution: 3.1→40.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2962 0 68 0 3030
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00273084
X-RAY DIFFRACTIONf_angle_d0.50864164
X-RAY DIFFRACTIONf_chiral_restr0.0416461
X-RAY DIFFRACTIONf_plane_restr0.0043526
X-RAY DIFFRACTIONf_dihedral_angle_d15.83591151
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1-3.260.3643530.2527505X-RAY DIFFRACTION34.08
3.26-3.470.25481300.22281142X-RAY DIFFRACTION76.64
3.47-3.740.27861510.22991338X-RAY DIFFRACTION89.56
3.74-4.110.23321490.1921347X-RAY DIFFRACTION89.98
4.11-4.710.2081500.17591349X-RAY DIFFRACTION89.87
4.71-5.920.18871570.17671337X-RAY DIFFRACTION89.49
5.93-40.760.22071500.18091362X-RAY DIFFRACTION89.55
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)
10.187467434325-0.05363771168210.1898613713740.544925342683-0.4086680155630.42761827878-0.1062165916320.1818061589230.0207462069422-0.265976354194-0.05810053555150.58449989149-0.258113759374-0.4656496716790.05750333786120.3036301123610.218233225008-0.2516876743730.616477011403-0.09945197112440.372392990571-23.900357917622.408876467-29.2900074986
21.08650052582-0.484811778696-0.3986287323890.961294414159-0.07867951836471.14665189364-0.1679704900470.170014928721-0.1735036449390.436514812201-0.1733263164180.5154000466540.385033664267-0.04308686182990.08693671785360.414952526240.171361943262-0.04406367432520.17314201538-0.3622251048820.242789075038-20.389217100317.2601697548-15.4877342631
31.08686440976-0.1105655926510.6008919867560.320426209624-0.009535175624941.18777524883-0.1495670530650.01812972300970.1869336519380.08921781475150.0107914703642-0.0927270300246-0.1061894648590.141106021393-0.09192537142130.307011063490.0936355574215-0.482982731980.206128018412-0.1269263061430.30403584074-6.6064267431324.0195629524-10.7298560942
42.10295858437-0.8792124935270.04765341948120.6166596049520.3100271625060.599737748277-0.1594010088990.0163304629536-0.5423733671670.05291144743250.02142589884210.2576888510270.4560267630340.2066945616890.0288171785270.8559076181830.299828693676-0.1159441953550.181174458590.01224960718890.264934650622-11.78242719718.7570951105-8.13952588511
52.60137943695-0.0323984156286-0.004529318732321.826232360790.5546308309511.45845151851-0.297373158279-0.492543188198-0.774703057340.785330207112-0.009226592958950.2478545380460.521292164929-0.0329873497890.2010280920831.018536429160.08526993165240.1900460610170.3609351978620.02840464619580.438392458441-17.75948198956.09544052566-3.4379042183
62.5334147376-0.705395488971-1.04064015090.922730614032-0.8263451427082.186261875130.275696008535-0.60530826034-0.06102635035051.07801564921-0.2463474899271.096882751880.108303383508-0.467712966925-0.04486790165170.913696481571-0.273266612520.5124972347520.653633715197-0.1890071210081.15329437133-33.15530568993.59787064701-8.85346698244
72.84382407388-1.150603687050.3291667250790.6195479173780.3605184963182.95232161082-0.238773833443-0.7555265106720.02681102070280.5716676032430.2436617156030.50165246096-0.068921126166-0.3674883713230.04928916711660.601239825791-0.02492325976360.5029525349270.543582183202-0.2997423791860.855012994736-32.212631977611.9595765237-6.17366337267
82.25396476701-1.32524997367-0.6447686327281.41205619968-0.9127276896422.80036163315-0.168864153758-0.598260633947-0.005706663615270.6923207518040.313095757210.86403477994-0.252000566043-0.50055943643-0.1056331382790.3567679088740.06917957882780.2249740630980.644658261235-0.2808989234160.91988973884-37.270363755721.1312080879-9.09243150813
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 193 )162 - 1931 - 32
22chain 'A' and (resid 194 through 282 )194 - 28233 - 121
33chain 'A' and (resid 283 through 299 )283 - 299122 - 138
44chain 'A' and (resid 300 through 356 )300 - 356139 - 195
55chain 'A' and (resid 357 through 474 )357 - 474196 - 283
66chain 'A' and (resid 475 through 495 )475 - 495284 - 304
77chain 'A' and (resid 496 through 528 )496 - 528305 - 337
88chain 'A' and (resid 529 through 565 )529 - 565338 - 374

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