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- PDB-9bkn: DHODH in complex with Ligand 16 -

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Basic information

Entry
Database: PDB / ID: 9bkn
TitleDHODH in complex with Ligand 16
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Dihydroorotate dehydrogenase / DHODH / oxidoreductase / inhibitor / oxidoreductase-inhibitor complex / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase activity / dihydroorotase activity / Pyrimidine biosynthesis / UDP biosynthetic process / 'de novo' UMP biosynthetic process / 'de novo' pyrimidine nucleobase biosynthetic process / mitochondrial inner membrane ...pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase activity / dihydroorotase activity / Pyrimidine biosynthesis / UDP biosynthetic process / 'de novo' UMP biosynthetic process / 'de novo' pyrimidine nucleobase biosynthetic process / mitochondrial inner membrane / mitochondrion / nucleoplasm / cytosol
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
: / ACETATE ION / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsShaffer, P.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML.
Authors: DeRatt, L.G. / Zhang, Z. / Pietsch, C. / Cisar, J.S. / Zhang, X. / Wang, W. / Tanner, A. / Matico, R. / Shaffer, P. / Jacoby, E. / Kazmi, F. / Shukla, N. / Bush, T.L. / Patrick, A. / ...Authors: DeRatt, L.G. / Zhang, Z. / Pietsch, C. / Cisar, J.S. / Zhang, X. / Wang, W. / Tanner, A. / Matico, R. / Shaffer, P. / Jacoby, E. / Kazmi, F. / Shukla, N. / Bush, T.L. / Patrick, A. / Philippar, U. / Attar, R. / Edwards, J.P. / Kuduk, S.D.
History
DepositionApr 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)41,42412
Polymers39,7821
Non-polymers1,64211
Water6,774376
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.744, 90.744, 122.457
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-875-

HOH

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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: 39782.395 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Production host: Escherichia coli (E. coli)
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 8 types, 387 molecules

#2: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#3: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#4: Chemical ChemComp-A1AQK / (2P,6P)-6-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-7-fluoro-2-(2-methylphenyl)-4-(propan-2-yl)isoquinolin-1(2H)-one


Mass: 436.479 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 376 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 3.66 Å3/Da
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.10 M NaAcetate pH=4.8, 2.0 M (NH4)2SO4, 30 % Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.3→78.62 Å / Num. obs: 142930 / % possible obs: 99.8 % / Redundancy: 5.7 % / CC1/2: 1 / Rmerge(I) obs: 0.035 / Rrim(I) all: 0.039 / Net I/σ(I): 23.21
Reflection shellResolution: 1.3→1.55 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 3.55 / Num. unique obs: 58162 / CC1/2: 0.899 / Rrim(I) all: 0.539 / % possible all: 99.9

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.3→78.62 Å / Cor.coef. Fo:Fc: 0.981 / Cor.coef. Fo:Fc free: 0.975 / SU B: 1.211 / SU ML: 0.021 / Cross valid method: THROUGHOUT / ESU R: 0.03 / ESU R Free: 0.032 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.15205 6723 4.7 %RANDOM
Rwork0.12884 ---
obs0.12993 136207 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.771 Å2
Baniso -1Baniso -2Baniso -3
1-0.13 Å20.06 Å20 Å2
2--0.13 Å2-0 Å2
3----0.41 Å2
Refinement stepCycle: LAST / Resolution: 1.3→78.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2797 0 108 376 3281
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0193069
X-RAY DIFFRACTIONr_bond_other_d0.0020.022992
X-RAY DIFFRACTIONr_angle_refined_deg1.752.0194180
X-RAY DIFFRACTIONr_angle_other_deg2.04936871
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8445398
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.92422.941136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.48615519
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7031530
X-RAY DIFFRACTIONr_chiral_restr0.1110.2463
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213526
X-RAY DIFFRACTIONr_gen_planes_other0.0090.02687
LS refinement shellResolution: 1.3→1.334 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 513 -
Rwork0.304 10011 -
obs--99.79 %

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