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- PDB-6lp6: Crystal structure of human DHODH in complex with inhibitor 1214 -

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Basic information

Entry
Database: PDB / ID: 6lp6
TitleCrystal structure of human DHODH in complex with inhibitor 1214
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-B6U / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.795 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)41,55915
Polymers39,7251
Non-polymers1,83414
Water5,675315
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area170 Å2
ΔGint-11 kcal/mol
Surface area14830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.605, 90.605, 123.057
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, 329 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-B6U / 3-[3,5-bis(fluoranyl)-4-[2-fluoranyl-5-(hydroxymethyl)phenyl]phenyl]benzo[f]benzotriazole-4,9-dione


Mass: 435.355 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H12F3N3O3 / 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.: 315 / 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: 3.67 Å3/Da / Density % sol: 66.49 %
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 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.795→50 Å / Num. obs: 54969 / % possible obs: 100 % / Redundancy: 10 % / CC1/2: 0.919 / Rpim(I) all: 0.064 / Net I/σ(I): 10.8
Reflection shellResolution: 1.795→1.84 Å / Num. unique obs: 3597 / CC1/2: 0.73 / Rpim(I) all: 0.331

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Processing

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

6j3b


Resolution: 1.795→37.379 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 15.84
RfactorNum. reflection% reflection
Rfree0.178 2784 5.2 %
Rwork0.1545 --
obs0.1557 53538 97.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 147.25 Å2 / Biso mean: 26.26 Å2 / Biso min: 7.6 Å2
Refinement stepCycle: final / Resolution: 1.795→37.379 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2774 0 218 315 3307
Biso mean--33.13 39.34 -
Num. residues----364
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072986
X-RAY DIFFRACTIONf_angle_d1.0964045
X-RAY DIFFRACTIONf_chiral_restr0.043444
X-RAY DIFFRACTIONf_plane_restr0.005526
X-RAY DIFFRACTIONf_dihedral_angle_d14.251111
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.7953-1.82630.2644770.236169065
1.8263-1.85950.25211230.2282232690
1.8595-1.89530.22811350.2037248897
1.8953-1.93390.22581780.1914251898
1.9339-1.9760.19871310.1783256299
1.976-2.0220.181410.16792562100
2.022-2.07250.19261590.1639255499
2.0725-2.12850.19771040.15322608100
2.1285-2.19120.15731410.14352607100
2.1912-2.26190.14341580.14312569100
2.2619-2.34270.17861280.13912591100
2.3427-2.43650.18221470.13592604100
2.4365-2.54740.14761550.13762576100
2.5474-2.68160.16721510.13762591100
2.6816-2.84960.16861510.13742607100
2.8496-3.06950.16981460.13972622100
3.0695-3.37820.15941240.13572642100
3.3782-3.86660.17071500.1337261799
3.8666-4.86990.16541550.1438264899
4.8699-37.3790.20781300.2007277298

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