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

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Basic information

Entry
Database: PDB / ID: 5mvc
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 / OROTIC ACID / Chem-Y9B / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 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
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 / 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)43,91411
Polymers42,6361
Non-polymers1,27710
Water5,188288
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2260 Å2
ΔGint-45 kcal/mol
Surface area14490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.190, 91.190, 122.645
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: 42636.414 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 BL21(DE3) (bacteria)
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 6 types, 298 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-Y9B / 4-oxidanyl-~{N}-[2,3,5,6-tetrakis(fluoranyl)-4-phenyl-phenyl]-1,2,5-thiadiazole-3-carboxamide


Mass: 369.294 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H7F4N3O2S
#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.: 5 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 288 / 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: 3.85 Å3/Da / Density % sol: 68.02 % / Mosaicity: 0.23 °
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: 1.85→78.973 Å / Num. all: 50919 / Num. obs: 50919 / % possible obs: 100 % / Redundancy: 9.3 % / Biso Wilson estimate: 15.05 Å2 / Rpim(I) all: 0.061 / Rrim(I) all: 0.186 / Rsym value: 0.176 / Net I/av σ(I): 4.1 / Net I/σ(I): 9.4 / Num. measured all: 471097
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value% possible all
1.85-1.958.70.6691.20.2410.7120.669100
1.95-2.079.10.5111.50.1790.5410.511100
2.07-2.219.80.38420.1290.4050.384100
2.21-2.399.80.3052.50.1020.3220.305100
2.39-2.629.30.2463.10.0850.260.246100
2.62-2.938.80.1814.10.0640.1920.181100
2.93-3.389.30.1265.70.0430.1330.126100
3.38-4.149.70.0887.90.030.0930.088100
4.14-5.858.60.07390.0260.0780.073100
5.85-29.8499.10.0699.10.0240.0730.06999.3

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Processing

Software
NameVersionClassification
SCALA3.3.21data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.22data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4YLW

4ylw


Resolution: 1.85→29.849 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 16.21
RfactorNum. reflection% reflection
Rfree0.1892 2522 4.96 %
Rwork0.1618 --
obs0.1631 50874 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 110.19 Å2 / Biso mean: 15.7472 Å2 / Biso min: 3.18 Å2
Refinement stepCycle: final / Resolution: 1.85→29.849 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2694 0 80 288 3062
Biso mean--12.02 25.15 -
Num. residues----352
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0162833
X-RAY DIFFRACTIONf_angle_d1.3113840
X-RAY DIFFRACTIONf_chiral_restr0.081428
X-RAY DIFFRACTIONf_plane_restr0.009503
X-RAY DIFFRACTIONf_dihedral_angle_d10.4811695
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 18 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.8501-1.88570.26091410.235826542795
1.8857-1.92410.29111330.222926392772
1.9241-1.9660.24991520.226212773
1.966-2.01170.21461540.186426712825
2.0117-2.0620.20431140.178126712785
2.062-2.11770.21400.167726812821
2.1177-2.180.2041270.153926502777
2.18-2.25040.17571220.145426802802
2.2504-2.33080.15431390.146826742813
2.3308-2.4240.17541380.151726562794
2.424-2.53430.21021610.152326672828
2.5343-2.66780.19111570.1626702827
2.6678-2.83490.20051230.159526882811
2.8349-3.05360.19931630.158126842847
3.0536-3.36050.17251430.157826932836
3.3605-3.84590.16851110.145227582869
3.8459-4.8420.15261460.142727452891
4.842-29.85290.1791580.172128503008

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