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- PDB-9bkm: DHODH in complex with Ligand 10 -

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Basic information

Entry
Database: PDB / ID: 9bkm
TitleDHODH in complex with Ligand 10
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: 2.08 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)41,49610
Polymers39,9851
Non-polymers1,5129
Water4,720262
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.018, 91.018, 121.995
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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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: 39984.664 Da / Num. of mol.: 1 / Fragment: residues 29-395
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 , 7 types, 271 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-A1AQM / (2M,6P)-2-(2-chloro-6-fluorophenyl)-6-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-7-fluoro-4-(propan-2-yl)isoquinolin-1(2H)-one


Mass: 474.888 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21ClF2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 262 / 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: 3.65 Å3/Da / Density % sol: 66.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.10 M NaAcetat_pH4.8, 2.30 M (NH4)2SO4, 30 % Glycerol, 18% (w/v) PEG 4000, 0.1M Na3Citrate pH=5.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99989 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 12, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99989 Å / Relative weight: 1
ReflectionResolution: 2.08→78.82 Å / Num. obs: 33919 / % possible obs: 95.1 % / Redundancy: 5.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.089 / Rrim(I) all: 0.099 / Net I/σ(I): 13.63
Reflection shellResolution: 2.08→2.33 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.498 / Mean I/σ(I) obs: 3.84 / Num. unique obs: 8974 / CC1/2: 0.937 / Rrim(I) all: 0.554 / % possible all: 88.4

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.08→78.82 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.926 / SU B: 7.846 / SU ML: 0.11 / Cross valid method: THROUGHOUT / ESU R: 0.161 / ESU R Free: 0.151 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22795 1564 4.6 %RANDOM
Rwork0.19063 ---
obs0.19238 32355 95.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.763 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å2-0.04 Å20 Å2
2---0.07 Å2-0 Å2
3---0.24 Å2
Refinement stepCycle: LAST / Resolution: 2.08→78.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2703 0 102 262 3067
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0192876
X-RAY DIFFRACTIONr_bond_other_d0.0040.022818
X-RAY DIFFRACTIONr_angle_refined_deg1.7392.023896
X-RAY DIFFRACTIONr_angle_other_deg1.33536458
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3975361
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.35722.923130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.68415486
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2881529
X-RAY DIFFRACTIONr_chiral_restr0.0990.2431
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213253
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02635
LS refinement shellResolution: 2.08→2.134 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 142 -
Rwork0.236 2434 -
obs--99.12 %
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)
14.402-0.0460.03161.44230.01914.5189-0.0413-0.2384-0.08240.3450.10070.41790.1773-0.2987-0.05940.2767-0.06980.07440.2130.05790.126823.514-23.26825.168
20.5390.11780.08731.71320.65451.6243-0.04190.09030.0116-0.12430.0348-0.014-0.026-0.01550.0070.1488-0.024-0.00630.1072-0.00390.001334.357-14.8997.589
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 70
2X-RAY DIFFRACTION2A71 - 400

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