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- PDB-5mut: Crystal structure of potent human Dihydroorotate Dehydrogenase in... -

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Basic information

Entry
Database: PDB / ID: 5mut
TitleCrystal structure of potent human Dihydroorotate Dehydrogenase inhibitors based on hydroxylated azole scaffolds
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE / dhodh / human dhodh
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 / FLAVIN MONONUCLEOTIDE / Chem-HYT / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
AuthorsGoyal, P. / Andersson, M. / Moritzer, A.C. / Sainas, S. / Pippione, A.C. / Boschi, D. / Al-Kadaraghi, S. / Lolli, M. / Friemann, R.
CitationJournal: Eur J Med Chem / Year: 2017
Title: Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.
Authors: Sainas, S. / Pippione, A.C. / Giorgis, M. / Lupino, E. / Goyal, P. / Ramondetti, C. / Buccinna, B. / Piccinini, M. / Braga, R.C. / Andrade, C.H. / Andersson, M. / Moritzer, A.C. / Friemann, ...Authors: Sainas, S. / Pippione, A.C. / Giorgis, M. / Lupino, E. / Goyal, P. / Ramondetti, C. / Buccinna, B. / Piccinini, M. / Braga, R.C. / Andrade, C.H. / Andersson, M. / Moritzer, A.C. / Friemann, R. / Mensa, S. / Al-Kadaraghi, S. / Boschi, D. / Lolli, M.L.
History
DepositionJan 14, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 8, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
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)40,8579
Polymers39,6541
Non-polymers1,2038
Water5,423301
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2010 Å2
ΔGint-25 kcal/mol
Surface area14580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.080, 91.080, 122.522
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: 39654.266 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Plasmid: pET-19b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 6 types, 309 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-HYT / 2-methyl-5-oxidanyl-~{N}-[2,3,5,6-tetrakis(fluoranyl)-4-phenyl-phenyl]-1,2,3-triazole-4-carboxamide


Mass: 366.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H10F4N4O2
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 301 / 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: 3.7 Å3/Da / Density % sol: 66.75 % / Mosaicity: 0.14 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 0.2M KBr, 0.2M KSCN, 0.1M NaAc pH 5.2, 25% PEG 400, 2% PGA-LM

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.87 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.87 Å / Relative weight: 1
ReflectionResolution: 1.75→78.878 Å / Num. obs: 59814 / % possible obs: 100 % / Redundancy: 18.5 % / Biso Wilson estimate: 11.12 Å2 / Rpim(I) all: 0.063 / Rrim(I) all: 0.275 / Rsym value: 0.268 / Net I/av σ(I): 2.6 / Net I/σ(I): 9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value% possible all
1.75-1.84180.7910.90.1910.8140.791100
1.84-1.9618.30.6921.10.1650.7120.692100
1.96-2.0919.90.5671.30.1290.5820.567100
2.09-2.2619.30.4451.70.1030.4570.445100
2.26-2.4717.50.36720.090.3780.367100
2.47-2.7717.90.2952.50.0710.3040.295100
2.77-3.219.40.2143.40.0490.2190.214100
3.2-3.9119.20.14250.0330.1460.142100
3.91-5.5316.90.1155.70.0290.1190.115100
5.53-26.80718.70.1195.10.0280.1230.11999.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.22data extraction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4YLW

4ylw


Resolution: 1.75→26.807 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 16.47
RfactorNum. reflection% reflection
Rfree0.1979 2910 4.87 %
Rwork0.1682 --
obs0.1696 59767 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 67.25 Å2 / Biso mean: 12.8739 Å2 / Biso min: 1.81 Å2
Refinement stepCycle: final / Resolution: 1.75→26.807 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2680 0 79 301 3060
Biso mean--8.88 22.34 -
Num. residues----350
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0172817
X-RAY DIFFRACTIONf_angle_d1.383818
X-RAY DIFFRACTIONf_chiral_restr0.093424
X-RAY DIFFRACTIONf_plane_restr0.01501
X-RAY DIFFRACTIONf_dihedral_angle_d10.941684
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 21 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.75-1.77870.28071580.250226662824
1.7787-1.80940.27971370.245626342771
1.8094-1.84230.26171310.235626992830
1.8423-1.87770.26461330.217526752808
1.8777-1.9160.22631360.206826772813
1.916-1.95760.22921330.190627012834
1.9576-2.00320.20181290.183326732802
2.0032-2.05320.22751280.170526932821
2.0532-2.10870.19541320.160927062838
2.1087-2.17080.19961230.157726952818
2.1708-2.24080.18831410.152426882829
2.2408-2.32080.19041520.155226932845
2.3208-2.41370.18341300.151126892819
2.4137-2.52350.17361250.150627102835
2.5235-2.65640.1791330.154427002833
2.6564-2.82270.18541720.158126932865
2.8227-3.04030.18331360.159327332869
3.0403-3.34580.18671550.158727062861
3.3458-3.82870.17681350.145327562891
3.8287-4.81920.16961430.148427722915
4.8192-26.81020.19531480.172628983046

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