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- PDB-8k4f: DHODH in complex with compound A0 -

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Basic information

Entry
Database: PDB / ID: 8k4f
TitleDHODH in complex with compound A0
ComponentsDihydroorotate dehydrogenase (quinone), mitochondrial
KeywordsOXIDOREDUCTASE / Inhibitor / complex
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-OG6 / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsJian, L. / Sun, Q.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82273850 China
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery and Optimization of Novel h DHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.
Authors: Zhou, X. / Gou, K. / Xu, J. / Jian, L. / Luo, Y. / Li, C. / Guan, X. / Qiu, J. / Zou, J. / Zhang, Y. / Zhong, X. / Zeng, T. / Zhou, Y. / Xiao, Y. / Yang, X. / Chen, W. / Gao, P. / Liu, C. / ...Authors: Zhou, X. / Gou, K. / Xu, J. / Jian, L. / Luo, Y. / Li, C. / Guan, X. / Qiu, J. / Zou, J. / Zhang, Y. / Zhong, X. / Zeng, T. / Zhou, Y. / Xiao, Y. / Yang, X. / Chen, W. / Gao, P. / Liu, C. / Zhou, Y. / Tao, L. / Liu, X. / Cen, X. / Chen, Q. / Sun, Q. / Luo, Y. / Zhao, Y.
History
DepositionJul 18, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 29, 2024Provider: 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)41,71214
Polymers39,8121
Non-polymers1,90013
Water5,603311
1
A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules

A: Dihydroorotate dehydrogenase (quinone), mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,42428
Polymers79,6252
Non-polymers3,79926
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_554-x,-x+y,-z-1/31
Buried area3570 Å2
ΔGint-60 kcal/mol
Surface area27760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.261, 91.261, 123.005
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 / DHOdehase / Dihydroorotate oxidase


Mass: 39812.418 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Production host: Escherichia coli (E. coli)
References: UniProt: Q02127, dihydroorotate dehydrogenase (quinone)

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Non-polymers , 8 types, 324 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#5: Chemical ChemComp-OG6 / 6-[bis(oxidanyl)methyl]-5~{H}-pyrimidine-2,4-dione / 6-Formyl-uracil hydrate


Mass: 158.112 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H6N2O4
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-FJW / 5-cyclopropyl-2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-amine / BAY 41-2272


Mass: 360.388 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17FN6 / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 311 / 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: 3.71 Å3/Da / Density % sol: 66.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M PH 4.6 CH3COONa, 1.6-2.0 M (NH4)2SO4, 30-36% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Aug 29, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.48→50.01 Å / Num. obs: 20687 / % possible obs: 97.1 % / Redundancy: 8.8 % / CC1/2: 0.985 / Net I/σ(I): 7.5
Reflection shellResolution: 2.48→2.62 Å / Num. unique obs: 3025 / CC1/2: 0.693

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Processing

Software
NameVersionClassification
REFMAC5.8.0403refinement
HKL-3000data scaling
HKL-3000data reduction
HKL-3000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.48→50.01 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.92 / SU B: 14.356 / SU ML: 0.142 / Cross valid method: THROUGHOUT / ESU R Free: 0.213 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20379 975 4.7 %RANDOM
Rwork0.15392 ---
obs0.15618 19725 96.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.521 Å2
Baniso -1Baniso -2Baniso -3
1--0.7 Å2-0.35 Å2-0 Å2
2---0.7 Å20 Å2
3---2.28 Å2
Refinement stepCycle: 1 / Resolution: 2.48→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2792 0 124 311 3227
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0123044
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162964
X-RAY DIFFRACTIONr_angle_refined_deg0.9471.6644123
X-RAY DIFFRACTIONr_angle_other_deg0.3181.586807
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1975382
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.609534
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.63910512
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0450.2455
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023653
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02699
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7982.7531510
X-RAY DIFFRACTIONr_mcbond_other0.7942.7461507
X-RAY DIFFRACTIONr_mcangle_it1.3234.9221896
X-RAY DIFFRACTIONr_mcangle_other1.3234.9241897
X-RAY DIFFRACTIONr_scbond_it0.8253.1381534
X-RAY DIFFRACTIONr_scbond_other0.8253.1381535
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.3125.6132225
X-RAY DIFFRACTIONr_long_range_B_refined4.74330.43588
X-RAY DIFFRACTIONr_long_range_B_other4.13327.913499
X-RAY DIFFRACTIONr_rigid_bond_restr1.3436008
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.48→2.544 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.233 66 -
Rwork0.205 1414 -
obs--95.48 %

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