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

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Basic information

Entry
Database: PDB / ID: 5mvd
TitleCrystal structure of potent human Dihydroorotate Dehydrogenase inhibitors based on hydroxylated azole scaffolds
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrialDihydroorotate dehydrogenase (quinone)
KeywordsOXIDOREDUCTASE / dhodh / human dhodh
Function / homology
Function and homology information


dihydroorotate dehydrogenase (quinone) / pyrimidine ribonucleotide biosynthetic process / 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 ...dihydroorotate dehydrogenase (quinone) / pyrimidine ribonucleotide biosynthetic process / 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 / integral component of membrane / nucleoplasm / cytosol
Similarity search - Function
Dihydroorotate dehydrogenase, class 2 / Dihydroorotate dehydrogenase signature 2. / Dihydroorotate dehydrogenase signature 1. / 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-U91 / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 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 16, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 8, 2017Provider: repository / Type: Initial release

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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)40,7129
Polymers39,4961
Non-polymers1,2168
Water4,197233
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2020 Å2
ΔGint-26 kcal/mol
Surface area14320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.850, 90.850, 122.924
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 / Dihydroorotate dehydrogenase (quinone) / DHOdehase / Dihydroorotate oxidase


Mass: 39496.105 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, 241 molecules

#2: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#3: Chemical ChemComp-ORO / OROTIC ACID / Orotic acid


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#4: Chemical ChemComp-U91 / 1,5-dimethyl-3-oxidanyl-~{N}-[2,3,5,6-tetrakis(fluoranyl)-4-phenyl-phenyl]pyrazole-4-carboxamide


Mass: 379.308 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H13F4N3O2
#5: Chemical ChemComp-ACT / ACETATE ION / Acetate


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


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


Mass: 18.015 Da / Num. of mol.: 233 / 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: 3.87 Å3/Da / Density % sol: 68.22 % / Mosaicity: 0.33 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 0.2M KBr, 0.2M KSCN, 0.1M NaAc pH 5.2, 35% PEG 400, 5% PGA-LM

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.872 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: 0.872 Å / Relative weight: 1
ReflectionResolution: 1.95→78.679 Å / Num. obs: 43390 / % possible obs: 100 % / Redundancy: 9.3 % / Biso Wilson estimate: 15.83 Å2 / Rpim(I) all: 0.069 / Rrim(I) all: 0.213 / Rsym value: 0.2 / Net I/av σ(I): 3.7 / Net I/σ(I): 9.2
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value
1.95-2.069.20.75210.260.7970.752
2.06-2.188.90.5621.40.1990.5970.562
2.18-2.339.20.441.70.1530.4660.44
2.33-2.5210.10.3712.10.1220.3910.371
2.52-2.769.80.2862.70.0950.3010.286
2.76-3.088.90.1963.90.0690.2080.196
3.08-3.569.20.1265.90.0440.1330.126
3.56-4.369.90.0898.10.030.0930.089
4.36-6.178.90.0798.60.0280.0840.079

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALA3.3.21data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.22data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4YLW
Resolution: 1.95→30.426 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 17.15
RfactorNum. reflection% reflection
Rfree0.2016 2100 4.84 %
Rwork0.1672 --
obs0.1689 43344 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 76.17 Å2 / Biso mean: 16.4273 Å2 / Biso min: 1.46 Å2
Refinement stepCycle: final / Resolution: 1.95→30.426 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2664 0 80 233 2977
Biso mean--17.95 24.13 -
Num. residues----348
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0162811
X-RAY DIFFRACTIONf_angle_d1.43814
X-RAY DIFFRACTIONf_chiral_restr0.08425
X-RAY DIFFRACTIONf_plane_restr0.009500
X-RAY DIFFRACTIONf_dihedral_angle_d12.0781687
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.95-1.99540.29231150.227727352850
1.9954-2.04530.25921410.208627252866
2.0453-2.10060.22471590.194626772836
2.1006-2.16240.22341530.179727132866
2.1624-2.23210.19881370.169626982835
2.2321-2.31190.2431550.167627142869
2.3119-2.40440.22911390.170327312870
2.4044-2.51380.18981300.163327522882
2.5138-2.64630.22791200.160227422862
2.6463-2.8120.20861130.168927812894
2.812-3.02890.19661470.164527392886
3.0289-3.33340.2011300.159927732903
3.3334-3.81490.19281540.150127472901
3.8149-4.80330.15831650.140927892954
4.8033-30.42930.17211420.177429283070

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