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- PDB-2fqi: dual binding modes of a novel series of DHODH inhibitors -

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Basic information

Entry
Database: PDB / ID: 2fqi
Titledual binding modes of a novel series of DHODH inhibitors
ComponentsDihydroorotate dehydrogenase, mitochondrial
KeywordsOXIDOREDUCTASE / protein inhibitor complex
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
ACETATE ION / FLAVIN MONONUCLEOTIDE / Chem-ILH / OROTIC ACID / Dihydroorotate dehydrogenase (quinone), mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsBaumgartner, R. / 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
DepositionJan 18, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydroorotate dehydrogenase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,6659
Polymers43,2221
Non-polymers1,4438
Water4,756264
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.431, 90.431, 123.003
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, mitochondrial / / Dihydroorotate oxidase / DHOdehase


Mass: 43222.082 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHODH / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q02127, EC: 1.3.3.1

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Non-polymers , 6 types, 272 molecules

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


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / 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-ILH / 2-({[2,3,5,6-TETRAFLUORO-3'-(TRIFLUOROMETHOXY)BIPHENYL-4-YL]AMINO}CARBONYL)CYCLOPENTA-1,3-DIENE-1-CARBOXYLIC ACID


Mass: 461.287 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H10F7NO4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 264 / 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: 3.36 Å3/Da / Density % sol: 63.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.7
Details: Drops were formed by mixing equal amounts of 20 mg/ml protein in 50 mM HEPES pH 7.7, 400 mM NaCl, 30% glycerol, 1 mM EDTA and 10 mM N,N-dimethylundecylamin-N-oxide (C11DAO) with a ...Details: Drops were formed by mixing equal amounts of 20 mg/ml protein in 50 mM HEPES pH 7.7, 400 mM NaCl, 30% glycerol, 1 mM EDTA and 10 mM N,N-dimethylundecylamin-N-oxide (C11DAO) with a precipitant solution of 0.1 M acetate pH 4.6 5.0, 40 mM C11DAO, 20.8 mM N,N-dimethyldecylamine-N-oxide (DDAO), 2 mM dihydroorotate (DHO), 1.8 2.4 M ammonium sulfate, 1 mM compound. The hanging drops were incubated against 0.5 mL reservoir of 0.1 M acetate pH 4.8, 2.4 2.6 M ammonium sulfate and 30% glycerol, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MPG/DESY, HAMBURG / Beamline: BW6 / Wavelength: 1.05 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 22, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.05 Å / Relative weight: 1
ReflectionResolution: 1.95→25 Å / Num. obs: 47164 / % possible obs: 99.8 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Biso Wilson estimate: 11.5 Å2 / Rmerge(I) obs: 0.082 / Net I/σ(I): 12.6
Reflection shellResolution: 1.95→2.05 Å / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 3.4 / Num. unique all: 42908 / % possible all: 99.9

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT1.701data extraction
MOSFLMdata reduction
CCP4(TRUNCATE)data scaling
MOLREPphasing
CNX2002refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1D3G.pdb

1d3g


Resolution: 1.95→19.9 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 2280849 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.202 4278 10 %RANDOM
Rwork0.185 ---
obs-47164 99.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 62.066 Å2 / ksol: 0.408 e/Å3
Displacement parametersBiso mean: 22.8 Å2
Baniso -1Baniso -2Baniso -3
1-1.4 Å21.51 Å20 Å2
2--1.4 Å20 Å2
3----2.8 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.21 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.16 Å0.11 Å
Refinement stepCycle: LAST / Resolution: 1.95→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2770 0 128 264 3162
Refine LS restraints
Refine-IDTypeDev idealWeight
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d21.2
X-RAY DIFFRACTIONc_improper_angle_d0.81
X-RAY DIFFRACTIONc_mcbond_it1.141.5
X-RAY DIFFRACTIONc_mcangle_it1.682
X-RAY DIFFRACTIONc_scbond_it2.052
X-RAY DIFFRACTIONc_scangle_it3.132.5
LS refinement shellResolution: 1.95→2.07 Å / Rfactor Rfree error: 0.009 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.236 710 10.1 %
Rwork0.206 6313 -
obs-7023 99.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein.topprotein_rep.param
X-RAY DIFFRACTION2water.topwater_rep.param
X-RAY DIFFRACTION3ion.topion.param
X-RAY DIFFRACTION4all_ligands.topall_ligands.par
X-RAY DIFFRACTION5cis_peptide.param

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