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- PDB-2bxv: Dual binding mode of a novel series of DHODH inhibitors -

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Basic information

Entry
Database: PDB / ID: 2bxv
TitleDual binding mode of a novel series of DHODH inhibitors
ComponentsDIHYDROOROTATE DEHYDROGENASE
KeywordsOXIDOREDUCTASE / DIHYDROOROTATE DEHYDROGENASE INHIBITOR / DUAL BINDING MODE / VIRTUAL HIGH-THROUGHPUT SCREENING / RHEUMATOID ARTHRITIS OXIDOREDUCTASE
Function / homology
Function and homology information


pyrimidine ribonucleotide biosynthetic process / dihydroorotate dehydrogenase (quinone) activity / dihydroorotate dehydrogenase (quinone) / 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) activity / dihydroorotate dehydrogenase (quinone) / 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 / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-3FT / ACETATE ION / FLAVIN MONONUCLEOTIDE / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsBaumgartner, R. / Walloschek, M. / Karlik, M. / Gotschlich, A. / Tasler, S. / Mies, J. / Leban, J.
CitationJournal: J. Med. Chem. / Year: 2006
Title: Dual binding mode of a novel series of DHODH inhibitors.
Authors: Baumgartner, R. / Walloschek, M. / Kralik, M. / Gotschlich, A. / Tasler, S. / Mies, J. / Leban, J.
History
DepositionJul 27, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2006Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 25, 2018Group: Data collection / Database references / Source and taxonomy
Category: citation / entity_src_gen / reflns_shell
Item: _citation.journal_abbrev / _citation.page_last ..._citation.journal_abbrev / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_strain / _reflns_shell.Rmerge_I_obs
Revision 1.4Mar 6, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp
Revision 1.5Dec 13, 2023Group: 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
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DIHYDROOROTATE DEHYDROGENASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,0336
Polymers39,8571
Non-polymers1,1775
Water3,477193
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)90.652, 90.652, 123.213
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 / / DIHYDROOROTATE OXIDASE / DHODEHASE


Mass: 39856.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET19B / Production host: ESCHERICHIA COLI BL21(DE3) (bacteria) / References: UniProt: Q02127, EC: 1.3.3.1

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Non-polymers , 6 types, 198 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE / Flavin mononucleotide


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#5: Chemical ChemComp-ORO / OROTIC ACID / Orotic acid


Mass: 156.096 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N2O4
#6: Chemical ChemComp-3FT / 2-({[3-FLUORO-3'-(TRIFLUOROMETHOXY)BIPHENYL-4-YL]AMINO}CARBONYL)CYCLOPENT-1-ENE-1-CARBOXYLIC ACID


Mass: 409.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15F4NO4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 193 / 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: 3.67 Å3/Da / Density % sol: 66.46 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.6
Details: AMMONIUM SULPHATE, ACETATE BUFFER, GLYCEROL, DDAO, C11DAO, A771726, OROTATE, VAPOR DIFFUSION, TEMPERATURE 293K, pH 4.60

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MPG/DESY, HAMBURG / Beamline: BW6 / Wavelength: 1.05
DetectorType: MARRESEARCH / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.05 Å / Relative weight: 1
ReflectionResolution: 2.15→19.94 Å / Num. obs: 32175 / % possible obs: 99.2 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 14.3 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 14.7
Reflection shellResolution: 2.15→2.28 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.248 / Mean I/σ(I) obs: 5.7 / % possible all: 99

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Processing

Software
NameClassification
CNSrefinement
MOSFLMdata reduction
CCP4data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1D3H

1d3h


Resolution: 2.15→19.94 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 2195233.92 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.223 3233 10.1 %RANDOM
Rwork0.203 ---
obs0.203 32161 99.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 53.3817 Å2 / ksol: 0.389889 e/Å3
Displacement parametersBiso mean: 23 Å2
Baniso -1Baniso -2Baniso -3
1-1.52 Å22.24 Å20 Å2
2--1.52 Å20 Å2
3----3.04 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.1 Å0.05 Å
Refinement stepCycle: LAST / Resolution: 2.15→19.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2744 0 80 193 3017
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d21.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.79
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.251.5
X-RAY DIFFRACTIONc_mcangle_it1.932
X-RAY DIFFRACTIONc_scbond_it1.992
X-RAY DIFFRACTIONc_scangle_it2.972.5
LS refinement shellResolution: 2.15→2.28 Å / Rfactor Rfree error: 0.009 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.212 531 10.1 %
Rwork0.192 4726 -
obs--98.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION5CIS_PEPTIDE.PARAM

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