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- PDB-6jmd: Crystal structure of human DHODH in complex with inhibitor 1223 -

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Basic information

Entry
Database: PDB / ID: 6jmd
TitleCrystal structure of human DHODH in complex with inhibitor 1223
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / DHODH / Inhibitor / Complex / OXIDOREDUCTASE / 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 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-BVO / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.781 Å
AuthorsYu, Y. / Chen, Q.
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
DepositionMar 8, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2020Group: 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 1.2Mar 27, 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)41,2959
Polymers39,7251
Non-polymers1,5698
Water4,900272
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area170 Å2
ΔGint-11 kcal/mol
Surface area14700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.627, 90.627, 123.169
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: 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 , 7 types, 280 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.: 2 / 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-BVO / 3-[3,5-bis(fluoranyl)-4-[3-(hydroxymethyl)phenyl]phenyl]benzo[f]benzotriazole-4,9-dione


Mass: 417.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H13F2N3O3 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 272 / 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: 3.68 Å3/Da / Density % sol: 66.54 %
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 PILATUS 6M / Detector: PIXEL / Date: Aug 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.78→50 Å / Num. obs: 56535 / % possible obs: 99.9 % / Redundancy: 10 % / CC1/2: 0.97 / Rpim(I) all: 0.05 / Rrim(I) all: 0.159 / Χ2: 1.001 / Net I/σ(I): 14.36
Reflection shellResolution: 1.78→1.82 Å

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementResolution: 1.781→48.45 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 15.7
RfactorNum. reflection% reflection
Rfree0.1768 1145 2.04 %
Rwork0.1547 --
obs0.1552 56052 99.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.781→48.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2773 0 107 272 3152
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082995
X-RAY DIFFRACTIONf_angle_d1.0984066
X-RAY DIFFRACTIONf_dihedral_angle_d14.5321125
X-RAY DIFFRACTIONf_chiral_restr0.04444
X-RAY DIFFRACTIONf_plane_restr0.006531
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7809-1.8620.19671450.20286449X-RAY DIFFRACTION95
1.862-1.96010.16981630.17486794X-RAY DIFFRACTION100
1.9601-2.08290.17031190.1596831X-RAY DIFFRACTION100
2.0829-2.24380.1781140.14636925X-RAY DIFFRACTION100
2.2438-2.46960.16721470.13946870X-RAY DIFFRACTION100
2.4696-2.82690.18271610.14366884X-RAY DIFFRACTION100
2.8269-3.56140.18361520.14186964X-RAY DIFFRACTION100
3.5614-48.46770.17271440.16417190X-RAY DIFFRACTION100

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