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- PDB-8vhl: Structure of DHODH in Complex with Ligand 17 -

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Basic information

Entry
Database: PDB / ID: 8vhl
TitleStructure of DHODH in Complex with Ligand 17
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / DIHYDROOROTATE DEHYDROGENASE / DHODH / OXIDOREDUCTASE / INHIBITOR / 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: 1.93 Å
AuthorsShaffer, P.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.
Authors: DeRatt, L.G. / Pietsch, E.C. / Cisar, J.S. / Jacoby, E. / Kazmi, F. / Matico, R. / Shaffer, P. / Tanner, A. / Wang, W. / Attar, R. / Edwards, J.P. / Kuduk, S.D.
History
DepositionJan 2, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release

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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)41,94114
Polymers39,9851
Non-polymers1,95613
Water5,206289
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, 122.713
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-789-

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: 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, 302 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-A1AA2 / N-(2-chloro-6-fluorophenyl)-4-[ethyl(2-hydroxyethyl)carbamamido]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide


Mass: 509.854 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21ClF5N3O4 / 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 289 / 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: 3.55 Å3/Da / Density % sol: 65.39 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.8
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: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 14, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.93→78.59 Å / Num. obs: 42552 / % possible obs: 95.6 % / Redundancy: 2.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.065 / Rrim(I) all: 0.084 / Net I/σ(I): 11.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.93-2.182.10.501127650.7290.6571
2.18-2.40.23475150.9060.3061
2.4-2.760.12974330.9690.1691
2.76-3.370.05566250.9950.0711
3.37-4.270.02740580.9980.0351
4.27-5.480.0221740.9980.0251
5.48-80.02213260.9980.0281
8-12.80.0154890.9990.0191
12.8-78.590.0171670.9990.0231

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 8DHG

8dhg


Resolution: 1.93→78.59 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.952 / SU B: 6.168 / SU ML: 0.089 / Cross valid method: THROUGHOUT / ESU R: 0.114 / ESU R Free: 0.111 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19903 2042 4.8 %RANDOM
Rwork0.16764 ---
obs0.16915 40510 95.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.087 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å2-0.05 Å2-0 Å2
2---0.11 Å20 Å2
3---0.34 Å2
Refinement stepCycle: LAST / Resolution: 1.93→78.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2712 0 127 289 3128
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0192959
X-RAY DIFFRACTIONr_bond_other_d0.0050.022867
X-RAY DIFFRACTIONr_angle_refined_deg1.992.0234012
X-RAY DIFFRACTIONr_angle_other_deg1.43736583
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1515372
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.89523.413126
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.0615.02492
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4391526
X-RAY DIFFRACTIONr_chiral_restr0.1190.2446
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213352
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02646
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.1762.4061473
X-RAY DIFFRACTIONr_mcbond_other3.1342.3961469
X-RAY DIFFRACTIONr_mcangle_it3.9754.0081848
X-RAY DIFFRACTIONr_mcangle_other3.9744.011849
X-RAY DIFFRACTIONr_scbond_it7.0193.1551485
X-RAY DIFFRACTIONr_scbond_other7.0083.1551485
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.1965.0172165
X-RAY DIFFRACTIONr_long_range_B_refined8.43124.2593467
X-RAY DIFFRACTIONr_long_range_B_other8.34723.2213380
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.93→1.98 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 128 -
Rwork0.308 2948 -
obs--94.53 %
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)
13.8364-0.3514-0.99473.82361.09853.9205-0.067-0.203-0.09750.22880.01490.32280.1531-0.32820.05220.2288-0.07490.06110.15320.03560.076623.386-23.06525.003
20.35080.08360.08911.80970.54191.7119-0.0510.0751-0.0245-0.12950.04720.01150.0124-0.00060.00390.1095-0.0269-0.00510.0763-0.00310.002634.406-14.8857.646
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 70
2X-RAY DIFFRACTION2A71 - 400

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