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- PDB-7z6c: Crystal structure of human Dihydroorotate Dehydrogenase in comple... -

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Basic information

Entry
Database: PDB / ID: 7z6c
TitleCrystal structure of human Dihydroorotate Dehydrogenase in complex with the inhibitor 2-Hydroxy-N-(2-ispropyl-5-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide.
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE / Dihydroorotate Dehydrogenase / inhibitor / complex / acute myeloid leukaemia.
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 / Chem-IEQ / 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. / Lolli, M.L. / Boschi, D. / Sainas, S. / Rizzi, M. / Ferraris, D.M. / Miggiano, R.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Ministry of EducationFAR_2017 Italy
CitationJournal: J.Med.Chem. / Year: 2022
Title: Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a ]pyridine Scaffold: SAR of the Aryloxyaryl Moiety.
Authors: Sainas, S. / Giorgis, M. / Circosta, P. / Poli, G. / Alberti, M. / Passoni, A. / Gaidano, V. / Pippione, A.C. / Vitale, N. / Bonanni, D. / Rolando, B. / Cignetti, A. / Ramondetti, C. / ...Authors: Sainas, S. / Giorgis, M. / Circosta, P. / Poli, G. / Alberti, M. / Passoni, A. / Gaidano, V. / Pippione, A.C. / Vitale, N. / Bonanni, D. / Rolando, B. / Cignetti, A. / Ramondetti, C. / Lanno, A. / Ferraris, D.M. / Canepa, B. / Buccinna, B. / Piccinini, M. / Rizzi, M. / Saglio, G. / Al-Karadaghi, S. / Boschi, D. / Miggiano, R. / Tuccinardi, T. / Lolli, M.L.
History
DepositionMar 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)41,0816
Polymers39,7251
Non-polymers1,3555
Water3,819212
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint8 kcal/mol
Surface area14910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.100, 91.100, 124.030
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
Details: The residues that do not match with the input sequence belong to the N-terminal tag inserted during subcloning procedure and they are not visible in the electron density.
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 6 types, 217 molecules

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


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-IEQ / ~{N}-(5-methyl-4-phenoxy-2-propan-2-yl-phenyl)-2-oxidanyl-pyrazolo[1,5-a]pyridine-3-carboxamide


Mass: 401.458 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23N3O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-P6G / HEXAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 282.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O7 / Comment: precipitant*YM
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 212 / 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: 3.74 Å3/Da / Density % sol: 67.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: Ammonium sulfate 2 M, 100 mM sodium acetate pH 4.8, 30% glycerol.

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Data collection

DiffractionMean temperature: 93 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→48.76 Å / Num. obs: 51366 / % possible obs: 99.9 % / Redundancy: 6.7 % / Biso Wilson estimate: 25.83 Å2 / Rmerge(I) obs: 0.113 / Net I/σ(I): 8.8
Reflection shellResolution: 1.85→1.95 Å / Rmerge(I) obs: 0.763 / Num. unique obs: 7438

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
SCALAdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6OC0

6oc0


Resolution: 1.85→45.55 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 19.31 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1902 2652 5.17 %
Rwork0.1771 48602 -
obs0.1778 51254 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 100.43 Å2 / Biso mean: 31.4075 Å2 / Biso min: 11.73 Å2
Refinement stepCycle: final / Resolution: 1.85→45.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2796 0 169 213 3178
Biso mean--32.83 40.66 -
Num. residues----366
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 19

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.85-1.880.24471200.24422544266499
1.88-1.920.29441230.238925102633100
1.92-1.960.23611680.2125092677100
1.96-20.22741240.197225302654100
2-2.050.22691400.185625302670100
2.05-2.10.22411230.188125642687100
2.1-2.160.2071200.190625382658100
2.16-2.220.18981320.179525472679100
2.22-2.290.20491510.169225182669100
2.29-2.370.20611270.174825412668100
2.37-2.470.18691330.172725762709100
2.47-2.580.17721400.174825502690100
2.58-2.720.20461500.174125352685100
2.72-2.890.191370.179125672704100
2.89-3.110.19311340.170925722706100
3.11-3.420.18411630.165125722735100
3.42-3.920.15581740.15925422716100
3.92-4.930.17351650.161926092774100
4.94-45.550.19651280.19422748287699

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