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- PDB-8rak: Crystal structure of human Dihydroorotate Dehydrogenase in comple... -

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Basic information

Entry
Database: PDB / ID: 8rak
TitleCrystal structure of human Dihydroorotate Dehydrogenase in complex with the inhibitor 2-Hydroxy-N-(2-isopropyl-5-methyl-4-(pyridin-4-yloxy)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsFLAVOPROTEIN / Drug discovery / DHODH / inhibitor / leukemia / protein binding
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-type TIM barrel
Similarity search - Domain/homology
ACETATE ION / FLAVIN MONONUCLEOTIDE / OROTIC ACID / : / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsAlberti, M. / Miggiano, R.
Funding support Italy, 1items
OrganizationGrant numberCountry
Other governmentDSF-FAR 2017 Italy
CitationJournal: Acta Crystallogr D Struct Biol / Year: 2024
Title: An alternative conformation of the N-terminal loop of human dihydroorotate dehydrogenase drives binding to a potent antiproliferative agent.
Authors: Alberti, M. / Poli, G. / Broggini, L. / Sainas, S. / Rizzi, M. / Boschi, D. / Ferraris, D.M. / Martino, E. / Ricagno, S. / Tuccinardi, T. / Lolli, M.L. / Miggiano, R.
History
DepositionDec 1, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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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)44,13911
Polymers42,6361
Non-polymers1,50210
Water5,260292
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2390 Å2
ΔGint-19 kcal/mol
Surface area15130 Å2
Unit cell
Length a, b, c (Å)91.474, 91.474, 124.032
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z
Components on special symmetry positions
IDModelComponents
11A-792-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Dihydroorotate dehydrogenase (quinone), mitochondrial


Mass: 42636.414 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The N-terminal sequence including the His-tag is not visible in the electron density.
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q02127

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Non-polymers , 6 types, 302 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-YMH / ~{N}-(5-methyl-2-propan-2-yl-4-pyridin-4-yloxy-phenyl)-2-oxidanyl-pyrazolo[1,5-a]pyridine-3-carboxamide


Mass: 402.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N4O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 292 / 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: 3.51 Å3/Da / Density % sol: 64.99 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 2M ammonium sulphate, 100 mM sodium acetate pH 4.8, and 30 % v/v glycerol

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Data collection

DiffractionMean temperature: 93.15 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8731 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Jan 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 1.85→48.83 Å / Num. obs: 51817 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 21.2 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.126 / Net I/σ(I): 9
Reflection shellResolution: 1.85→1.95 Å / Rmerge(I) obs: 0.726 / Num. unique obs: 7488 / CC1/2: 0.743

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→39.61 Å / SU ML: 0.1903 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.1984
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1861 2678 5.18 %
Rwork0.1643 49068 -
obs0.1655 51746 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.22 Å2
Refinement stepCycle: LAST / Resolution: 1.85→39.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2796 0 102 292 3190
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00872974
X-RAY DIFFRACTIONf_angle_d0.9294031
X-RAY DIFFRACTIONf_chiral_restr0.0599444
X-RAY DIFFRACTIONf_plane_restr0.0141530
X-RAY DIFFRACTIONf_dihedral_angle_d8.0371450
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.880.27341300.25882564X-RAY DIFFRACTION99.89
1.88-1.920.27681300.2382552X-RAY DIFFRACTION100
1.92-1.960.2651590.20972536X-RAY DIFFRACTION99.78
1.96-20.21851300.18982587X-RAY DIFFRACTION99.85
2-2.050.22951360.17192537X-RAY DIFFRACTION99.93
2.05-2.10.21431230.17152559X-RAY DIFFRACTION99.96
2.1-2.160.18541120.17042568X-RAY DIFFRACTION100
2.16-2.220.18851450.16522564X-RAY DIFFRACTION100
2.22-2.290.19341560.16412564X-RAY DIFFRACTION99.85
2.29-2.370.18731270.16752577X-RAY DIFFRACTION100
2.37-2.470.17941330.16312573X-RAY DIFFRACTION100
2.47-2.580.17851320.16212572X-RAY DIFFRACTION99.96
2.58-2.720.19291520.16572577X-RAY DIFFRACTION100
2.72-2.890.2091440.16042572X-RAY DIFFRACTION99.82
2.89-3.110.16131360.15022591X-RAY DIFFRACTION99.93
3.11-3.420.1831610.1492587X-RAY DIFFRACTION99.85
3.42-3.920.15041790.13712569X-RAY DIFFRACTION99.71
3.92-4.930.16461630.14222639X-RAY DIFFRACTION100
4.93-39.610.19521300.18782780X-RAY DIFFRACTION99.76

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