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- PDB-6lp8: Crystal structure of human DHODH in complex with inhibitor 1243 -

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Basic information

Entry
Database: PDB / ID: 6lp8
TitleCrystal structure of human DHODH in complex with inhibitor 1243
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE / DHODH / inhibitor
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
ACETATE ION / Chem-B6O / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsChen, Q. / Yu, Y.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Bifunctional Naphtho[2,3- d ][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.
Authors: Zuo, Z. / Liu, X. / Qian, X. / Zeng, T. / Sang, N. / Liu, H. / Zhou, Y. / Tao, L. / Zhou, X. / Su, N. / Yu, Y. / Chen, Q. / Luo, Y. / Zhao, Y.
History
DepositionJan 9, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)41,55415
Polymers39,7251
Non-polymers1,82914
Water5,044280
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: scanning transmission electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-11 kcal/mol
Surface area14790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.558, 90.558, 122.427
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 / DHOdehase / Dihydroorotate oxidase


Mass: 39725.344 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, 294 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-LDA / LAURYL DIMETHYLAMINE-N-OXIDE


Mass: 229.402 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C14H31NO / Comment: LDAO, detergent*YM
#7: Chemical ChemComp-B6O / 3-[4-[3-(dimethylamino)phenyl]-3,5-bis(fluoranyl)phenyl]benzo[f]benzotriazole-4,9-dione


Mass: 430.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H16F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 280 / 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: 66.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: hepes pH4.6 2M AMMONIUM SULPHATE 30%Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.79→50 Å / Num. obs: 55261 / % possible obs: 99.9 % / Redundancy: 10.1 % / Biso Wilson estimate: 17.8 Å2 / CC1/2: 0.989 / Rpim(I) all: 0.033 / Net I/σ(I): 21.5
Reflection shellResolution: 1.79→1.83 Å / Num. unique obs: 3640 / CC1/2: 0.942

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.8.4_1496refinement
PDB_EXTRACT3.25data extraction
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6J3B

6j3b


Resolution: 1.79→48.255 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 16.66
RfactorNum. reflection% reflection
Rfree0.1743 1117 2.02 %
Rwork0.1569 --
obs0.1572 55196 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 142.09 Å2 / Biso mean: 25.73 Å2 / Biso min: 6.96 Å2
Refinement stepCycle: final / Resolution: 1.79→48.255 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2785 0 198 280 3263
Biso mean--30.31 34.67 -
Num. residues----365
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072986
X-RAY DIFFRACTIONf_angle_d1.0834045
X-RAY DIFFRACTIONf_chiral_restr0.04444
X-RAY DIFFRACTIONf_plane_restr0.006527
X-RAY DIFFRACTIONf_dihedral_angle_d13.9441111
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.7902-1.87170.19851410.18576663
1.8717-1.97040.18271630.16376690
1.9704-2.09380.18311080.15716682
2.0938-2.25550.15991070.14856776
2.2555-2.48250.18961500.14826697
2.4825-2.84170.17861630.15186743
2.8417-3.580.16521440.14766803
3.58-48.2550.16751410.16527025

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