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- PDB-8dhf: DHODH IN COMPLEX WITH LIGAND 11 -

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Basic information

Entry
Database: PDB / ID: 8dhf
TitleDHODH IN COMPLEX WITH LIGAND 11
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrialDihydroorotate dehydrogenase (quinone)
KeywordsOXIDOREDUCTASE/INHIBITOR / DIHYDROOROTATE DEHYDROGENASE / DHODH / OXIDOREDUCTASE / INHIBITOR / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase (quinone) / 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) activity / dihydroorotate dehydrogenase (quinone) / 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 / Chem-T6L / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsShaffer, P.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: N -Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia.
Authors: Cisar, J.S. / Pietsch, C. / DeRatt, L.G. / Jacoby, E. / Kazmi, F. / Keohane, C. / Legenski, K. / Matico, R. / Shaffer, P. / Simonnet, Y. / Tanner, A. / Wang, C.Y. / Wang, W. / Attar, R. / ...Authors: Cisar, J.S. / Pietsch, C. / DeRatt, L.G. / Jacoby, E. / Kazmi, F. / Keohane, C. / Legenski, K. / Matico, R. / Shaffer, P. / Simonnet, Y. / Tanner, A. / Wang, C.Y. / Wang, W. / Attar, R. / Edwards, J.P. / Kuduk, S.D.
History
DepositionJun 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)42,57221
Polymers39,9851
Non-polymers2,58820
Water3,027168
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: scanning transmission electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.850, 90.850, 123.667
Angle α, β, γ (deg.)90.000, 90.000, 120.000
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 / Dihydroorotate dehydrogenase (quinone) / DHOdehase / Dihydroorotate oxidase


Mass: 39984.664 Da / Num. of mol.: 1 / Fragment: TRUNCATED
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, 188 molecules

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


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


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#4: Chemical ChemComp-T6L / (6M)-N-(2-chloro-6-fluorophenyl)-6-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}pyridine-3-carboxamide


Mass: 521.825 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17ClF5N5O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 168 / 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: 3.58 Å3/Da / Density % sol: 65.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.8
Details: 0.10 M Sodium Acetate pH 4.8, 2.30 M (NH4)2SO4, 30% Glycerol, 18% (w/v) PEG 4000, 0.1M Trisodium Citrate pH 5.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999880850315 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999880850315 Å / Relative weight: 1
ReflectionResolution: 1.78→78.68 Å / Num. obs: 56905 / % possible obs: 99.1 % / Redundancy: 3.5 % / Biso Wilson estimate: 26.04 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.051 / Rrim(I) all: 0.06 / Χ2: 0.989 / Net I/σ(I): 15.79
Reflection shellResolution: 1.78→2.03 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.475 / Mean I/σ(I) obs: 3.02 / Num. unique obs: 18432 / CC1/2: 0.854 / Rrim(I) all: 0.559 / % possible all: 99.7

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1D3G

1d3g


Resolution: 1.78→78.68 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.964 / SU B: 3.703 / SU ML: 0.058 / SU R Cruickshank DPI: 0.0793 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.079 / ESU R Free: 0.078 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.1808 2690 4.8 %RANDOM
Rwork0.1617 ---
obs0.1625 53931 99.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 113.45 Å2 / Biso mean: 33.061 Å2 / Biso min: 15.74 Å2
Baniso -1Baniso -2Baniso -3
1--0.22 Å2-0.11 Å2-0 Å2
2---0.22 Å20 Å2
3---0.71 Å2
Refinement stepCycle: final / Resolution: 1.78→78.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2707 0 170 169 3046
Biso mean--44.66 45.71 -
Num. residues----355
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192921
X-RAY DIFFRACTIONr_bond_other_d0.0040.022844
X-RAY DIFFRACTIONr_angle_refined_deg1.5672.0373958
X-RAY DIFFRACTIONr_angle_other_deg1.26936521
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0125368
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.28923.162117
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.85915474
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8231527
X-RAY DIFFRACTIONr_chiral_restr0.0880.2450
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213249
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02622
LS refinement shellResolution: 1.78→1.826 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 209 -
Rwork0.301 3926 -
all-4135 -
obs--99.07 %
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)
14.5360.1866-0.47563.69030.5664.3544-0.0912-0.2933-0.02540.23210.02730.55120.0824-0.54680.06380.2901-0.05750.06050.24020.04460.119422.603-23.43924.724
20.59480.15490.09541.72790.41561.6408-0.05970.0746-0.0107-0.09730.024-0.0073-0.0066-0.00740.03570.1322-0.022-0.00440.1106-0.00250.001534.586-14.7947.809
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A31 - 69
2X-RAY DIFFRACTION2A74 - 396

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