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

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Basic information

Entry
Database: PDB / ID: 9dko
TitleCrystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM1010 (6-cyclopropyl-2,4-dimethyl-3-(4-(trifluoromethyl)benzyl)-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 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 9, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3624
Polymers45,3861
Non-polymers9763
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)85.203, 85.203, 140.127
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-A1A5P / 6-cyclopropyl-2,4-dimethyl-3-{[4-(trifluoromethyl)phenyl]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one


Mass: 361.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18F3N3O / 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: 3.24 Å3/Da / Density % sol: 61.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5 / Details: 1.6 M Ammonium sulfate, 0.1 M Citric Acid pH 5.0

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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: 0.18
ReflectionResolution: 2.85→50 Å / Num. obs: 13408 / % possible obs: 99.9 % / Redundancy: 11.3 % / CC1/2: 1 / Net I/σ(I): 26.3
Reflection shellResolution: 2.85→2.9 Å / Mean I/σ(I) obs: 1.13 / Num. unique obs: 663 / CC1/2: 0.519 / % 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: 3→42.6 Å / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 27.5522
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2348 1067 10.22 %
Rwork0.1961 9374 -
obs0.2008 10441 90.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.47 Å2
Refinement stepCycle: LAST / Resolution: 3→42.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2980 0 68 0 3048
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00233103
X-RAY DIFFRACTIONf_angle_d0.45334190
X-RAY DIFFRACTIONf_chiral_restr0.0408463
X-RAY DIFFRACTIONf_plane_restr0.0047529
X-RAY DIFFRACTIONf_dihedral_angle_d15.08211157
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.140.3518690.2458588X-RAY DIFFRACTION40.47
3.14-3.30.29221110.2337977X-RAY DIFFRACTION68.61
3.3-3.510.27191470.21331303X-RAY DIFFRACTION89.55
3.51-3.780.25761400.20441300X-RAY DIFFRACTION90.28
3.78-4.160.23251440.18851288X-RAY DIFFRACTION89.94
4.16-4.760.19971500.17271304X-RAY DIFFRACTION89.68
4.76-60.19911430.19161306X-RAY DIFFRACTION90.13
6-42.60.23441490.19281322X-RAY DIFFRACTION89.69
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)
12.936347647640.6614613966621.043479427562.39720540395-0.7163187645581.45860929277-0.0916722418644-0.0949842745969-0.6550960099940.3517465648820.0321329292578-0.7165191597520.2484460935340.3667734140560.07347527301030.4637345460410.313167762287-0.1223482304050.6849017005240.0925621952630.57125167856132.4315367024-9.6876641630718.2065316498
21.498302109270.0345676925134-0.7880886014071.52935401870.1629485786952.79116661282-0.2345791408130.156261409423-0.419552262603-0.09223874023990.0188794014436-0.2664497883720.08273653720120.1773753429020.08490302207020.22836453641-0.08319974240660.1794246817960.5486283881450.004100446253560.22690433705727.2408327378-7.201435729612.27784841631
32.042692142570.324689813277-0.8337779664273.04410145267-1.022247941042.11312442856-0.2127443321620.0566541940587-0.2295602188030.269791366249-0.165582038747-0.0711975557470.148770740496-0.1596549247770.1296412210490.174902285975-0.0446526987410.0715179682430.520878005810.1522830981060.25223933047320.8446858112-5.035077564237.47405776364
42.599340323370.283759371411-0.3621612598180.924010539597-0.25379303570.532948440544-0.2019251106940.511817311918-0.302632648312-0.0892379077275-0.06519598088640.1889119995680.177491098346-0.424418663356-0.08718827613330.233038270646-0.2570357589490.03627671572091.050946948310.007462001842910.29805119751512.1191236781-5.83101231395-5.30739189545
51.04721968466-0.027519355757-0.6377262675742.71208255086-0.7839646509511.7627258945-0.2572228972421.604242019680.636977352734-0.4222447044440.1131997892450.0709148755372-0.0718013358178-0.3728995087740.07830100348450.463728120691-0.321432693143-0.05767564287111.334259869190.2529956329780.49821735125922.64724303275.62768762989-14.8963696779
62.246316210150.4953668758190.401183199021.766246378720.02466821758870.543645578325-0.2849250196930.479832477225-1.27320298188-0.3705664585680.269763645406-0.07833819384130.804099093462-0.4937269750070.01743860558930.628340063597-0.3842858607840.2667167626320.727258649153-0.2134210814370.90833304014114.6202188331-23.4744117789-1.30660143825
71.53011693011-0.8182551002750.6591693428710.481963085201-0.0468996382552.2402741089-0.2414524057060.769454914286-0.872407533414-0.205673050088-0.0162650883724-0.0926850307560.7262822473220.5321637130910.3345323878620.5848690798050.03504037071750.4997440843770.596622925643-0.1217248955830.8982437022632.1619992685-21.8610146162-2.62054160431
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 160 through 193 )160 - 1931 - 34
22chain 'A' and (resid 194 through 262 )194 - 26235 - 103
33chain 'A' and (resid 263 through 299 )263 - 299104 - 140
44chain 'A' and (resid 300 through 376 )300 - 376141 - 217
55chain 'A' and (resid 377 through 424 )377 - 424218 - 235
66chain 'A' and (resid 425 through 495 )425 - 495236 - 306
77chain 'A' and (resid 496 through 565 )496 - 565307 - 376

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