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- PDB-9ez9: Crystal structure of human Dihydroorotate Dehydrogenase in comple... -

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Basic information

Entry
Database: PDB / ID: 9ez9
TitleCrystal structure of human Dihydroorotate Dehydrogenase in complex with the inhibitor N-(3'-(2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-2-hydroxypyrazolo[1,5-a]pyridine-3-carboxamide
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE / Acute myelogenous leukemia Dihydroorotate dehydrogenase Inhibitors Drug Discovery
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
: / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsAlberti, M. / Miggiano, R.
Funding support Italy, 1items
OrganizationGrant numberCountry
Ministero dell Universita e della Ricerca Italy
CitationJournal: To Be Published
Title: Crystal structure of human Dihydroorotate Dehydrogenase in complex with the inhibitor N-(3'-(2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-2-hydroxypyrazolo[1,5-a]pyridine-3-carboxamide
Authors: Alberti, M. / Miggiano, R.
History
DepositionApr 11, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 23, 2025Provider: 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)44,1236
Polymers42,6361
Non-polymers1,4865
Water1,60389
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint-11 kcal/mol
Surface area14630 Å2
Unit cell
Length a, b, c (Å)91.071, 91.071, 123.441
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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


Mass: 42636.414 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The missing region refers to the N-terminal Histidine tag, whose density quality is very low.
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, 94 molecules

#2: Chemical ChemComp-ORO / OROTIC ACID


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#4: 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
#5: Chemical ChemComp-A1H8I / N-[4-[3-[2,2-bis(fluoranyl)propoxy]phenyl]-2,3,5,6-tetrakis(fluoranyl)phenyl]-2-oxidanyl-pyrazolo[1,5-a]pyridine-3-carboxamide / N-(3'-(2,2-difluoropropoxy)-2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-2-hydroxypyrazolo[1,5-a]pyridine-3-carboxamide


Mass: 495.374 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H15F6N3O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 3.47 Å3/Da / Density % sol: 64.51 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 2 M ammonium sulphate, 100 mM sodium acetate pH 4.8 and 20 % v/v glycerol

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Data collection

DiffractionMean temperature: 83.15 K / Ambient temp details: 83.15 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.6→48.61 Å / Num. obs: 18434 / % possible obs: 98.6 % / Redundancy: 5.8 % / CC1/2: 0.978 / Rmerge(I) obs: 0.24 / Net I/σ(I): 2
Reflection shellResolution: 2.6→2.74 Å / Num. unique obs: 2643 / CC1/2: 0.661

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
SCALAdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→41.15 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2325 921 5.01 %
Rwork0.1764 --
obs0.1792 18387 98.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.6→41.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2892 0 5 89 2986
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01
X-RAY DIFFRACTIONf_angle_d1.229
X-RAY DIFFRACTIONf_dihedral_angle_d10.346435
X-RAY DIFFRACTIONf_chiral_restr0.063442
X-RAY DIFFRACTIONf_plane_restr0.011522
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.740.35231300.23162458X-RAY DIFFRACTION99
2.74-2.910.28151360.21122447X-RAY DIFFRACTION99
2.91-3.130.29261510.21692450X-RAY DIFFRACTION98
3.13-3.450.24541150.17482473X-RAY DIFFRACTION98
3.45-3.950.20241290.16092513X-RAY DIFFRACTION99
3.95-4.970.16021140.14712526X-RAY DIFFRACTION98
4.97-41.150.23581460.17462599X-RAY DIFFRACTION97

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