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- PDB-6gk0: HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH CLASS III HIST... -

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Basic information

Entry
Database: PDB / ID: 6gk0
TitleHUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH CLASS III HISTONE DEACETYLASE INHIBITOR
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsANTITUMOR PROTEIN / Dehydrogenase DHODH tumor-killing drug development
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 class I / Aldolase-type TIM barrel / TIM Barrel ...Dihydroorotate dehydrogenase, class 2 / Dihydroorotate dehydrogenase signature 1. / Dihydroorotate dehydrogenase signature 2. / Dihydroorotate dehydrogenase, conserved site / : / Dihydroorotate dehydrogenase domain / Dihydroorotate dehydrogenase / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
ACETIC ACID / DECYLAMINE-N,N-DIMETHYL-N-OXIDE / Chem-DOR / Chem-F1W / FLAVIN MONONUCLEOTIDE / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.85 Å
AuthorsHakansson, M. / Ladds, M.J.G.W. / Walse, B. / Lain, S.
CitationJournal: J.Biol.Chem. / Year: 2020
Title: Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology.
Authors: Ladds, M.J.G.W. / Popova, G. / Pastor-Fernandez, A. / Kannan, S. / van Leeuwen, I.M.M. / Hakansson, M. / Walse, B. / Tholander, F. / Bhatia, R. / Verma, C.S. / Lane, D.P. / Lain, S.
History
DepositionMay 17, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)41,97516
Polymers39,8571
Non-polymers2,11915
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2850 Å2
ΔGint-57 kcal/mol
Surface area14790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.524, 90.524, 122.806
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-828-

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: 39856.535 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 , 9 types, 243 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-DOR / (4S)-2,6-DIOXOHEXAHYDROPYRIMIDINE-4-CARBOXYLIC ACID / DIHYDROOROTIC ACID


Mass: 158.112 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H6N2O4
#4: Chemical
ChemComp-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H4O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / 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-DDQ / DECYLAMINE-N,N-DIMETHYL-N-OXIDE


Mass: 201.349 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H27NO
#9: Chemical ChemComp-F1W / 4-~{tert}-butyl-~{N}-[[4-[5-(dimethylamino)pentanoylamino]phenyl]carbamothioyl]benzamide


Mass: 454.628 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34N4O2S
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 228 / Source method: isolated from a natural source / Formula: H2O

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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: 3.64 Å3/Da / Density % sol: 66.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.8
Details: 30% glycerol, 100 mM sodium acetate pH 4.8, 1.8 M Ammoniumsulphate, 40 mM DDAO, 6.4 mM C11DAO, 2 mM L-DHO, 1 mM Tenovin

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-3 / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→20 Å / Num. obs: 50141 / % possible obs: 99.8 % / Redundancy: 4.5 % / Net I/σ(I): 5.4
Reflection shellResolution: 1.85→1.89 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementResolution: 1.85→19.81 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.946 / SU B: 5.548 / SU ML: 0.079 / Cross valid method: THROUGHOUT / ESU R: 0.096 / ESU R Free: 0.095 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19301 2540 5.1 %RANDOM
Rwork0.16801 ---
obs0.16927 47568 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 29.791 Å2
Baniso -1Baniso -2Baniso -3
1-0.41 Å20.21 Å20 Å2
2--0.41 Å20 Å2
3----1.33 Å2
Refinement stepCycle: 1 / Resolution: 1.85→19.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2773 0 136 228 3137
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0143033
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172812
X-RAY DIFFRACTIONr_angle_refined_deg2.0151.7144118
X-RAY DIFFRACTIONr_angle_other_deg1.0831.6776606
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8165385
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.73320.562160
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.99615518
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5251531
X-RAY DIFFRACTIONr_chiral_restr0.110.2379
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.023430
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02517
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_it1.5591.6631485
X-RAY DIFFRACTIONr_mcbond_other1.5191.6541480
X-RAY DIFFRACTIONr_mcangle_it2.4712.4771860
X-RAY DIFFRACTIONr_mcangle_other2.4582.4681858
X-RAY DIFFRACTIONr_scbond_it2.8062.2341547
X-RAY DIFFRACTIONr_scbond_other2.8052.2361548
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.4473.1952249
X-RAY DIFFRACTIONr_long_range_B_refined7.67721.4793489
X-RAY DIFFRACTIONr_long_range_B_other7.67621.4823490
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.301 193 -
Rwork0.305 3460 -
obs--99.51 %
Refinement TLS params.Method: refined / Origin x: 2.837 Å / Origin y: 36.774 Å / Origin z: 10.83 Å
111213212223313233
T0.0065 Å20.0017 Å2-0.007 Å2-0.036 Å2-0.0031 Å2--0.015 Å2
L1.4801 °2-0.5889 °2-0.7134 °2-1.09 °2-0.0175 °2--1.6923 °2
S0.0011 Å °-0.0183 Å °-0.0414 Å °-0.0713 Å °-0.0211 Å °0.115 Å °0.0435 Å °-0.148 Å °0.0199 Å °

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