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- PDB-3sfi: Ethionamide Boosters Part 2: Combining Bioisosteric Replacement a... -

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Basic information

Entry
Database: PDB / ID: 3sfi
TitleEthionamide Boosters Part 2: Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.
ComponentsTranscriptional regulatory repressor protein (TETR-family)
KeywordsTRANSCRIPTION REPRESSOR/INHIBITOR / TETR-FAMILY / TRANSCRITPTIONAL REGULATORY REPRESSOR / INHIBITOR / DNA / DNA BINDING PROTEIN / TRANSCRIPTION REPRESSOR-INHIBITOR complex
Function / homology
Function and homology information


transcription cis-regulatory region binding / DNA-binding transcription factor activity / response to antibiotic / negative regulation of DNA-templated transcription / regulation of DNA-templated transcription / cytosol
Similarity search - Function
: / Transcriptional regulator EthR, C-terminal domain / : / Tetracycline Repressor, domain 2 / Tetracyclin repressor-like, C-terminal domain superfamily / Tetracycline Repressor; domain 2 / Bacterial regulatory proteins, tetR family / DNA-binding HTH domain, TetR-type / TetR-type HTH domain profile. / Homeodomain-like ...: / Transcriptional regulator EthR, C-terminal domain / : / Tetracycline Repressor, domain 2 / Tetracyclin repressor-like, C-terminal domain superfamily / Tetracycline Repressor; domain 2 / Bacterial regulatory proteins, tetR family / DNA-binding HTH domain, TetR-type / TetR-type HTH domain profile. / Homeodomain-like / Homeobox-like domain superfamily / Arc Repressor Mutant, subunit A / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-3SF / HTH-type transcriptional regulator EthR / HTH-type transcriptional regulator EthR
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 Å
AuthorsFlipo, M. / Desroses, M. / Lecat-Guillet, N. / Villemagne, B. / Blondiaux, N. / Leroux, F. / Piveteau, C. / Mathys, V. / Flament, M.P. / Siepmann, J. ...Flipo, M. / Desroses, M. / Lecat-Guillet, N. / Villemagne, B. / Blondiaux, N. / Leroux, F. / Piveteau, C. / Mathys, V. / Flament, M.P. / Siepmann, J. / Villeret, V. / Wohlkonig, A. / Wintjens, R. / Soror, S.H. / Christophe, T. / Jeon, H.K. / Locht, C. / Brodin, P. / D prez, B. / Baulard, A.R. / Willand, N.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.
Authors: Flipo, M. / Desroses, M. / Lecat-Guillet, N. / Villemagne, B. / Blondiaux, N. / Leroux, F. / Piveteau, C. / Mathys, V. / Flament, M.P. / Siepmann, J. / Villeret, V. / Wohlkonig, A. / ...Authors: Flipo, M. / Desroses, M. / Lecat-Guillet, N. / Villemagne, B. / Blondiaux, N. / Leroux, F. / Piveteau, C. / Mathys, V. / Flament, M.P. / Siepmann, J. / Villeret, V. / Wohlkonig, A. / Wintjens, R. / Soror, S.H. / Christophe, T. / Jeon, H.K. / Locht, C. / Brodin, P. / Deprez, B. / Baulard, A.R. / Willand, N.
History
DepositionJun 13, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2011Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2012Group: Database references
Revision 1.2Apr 9, 2014Group: Source and taxonomy
Revision 1.3Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.4Sep 13, 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: Transcriptional regulatory repressor protein (TETR-family)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,3272
Polymers25,9531
Non-polymers3741
Water543
1
A: Transcriptional regulatory repressor protein (TETR-family)
hetero molecules

A: Transcriptional regulatory repressor protein (TETR-family)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,6554
Polymers51,9062
Non-polymers7492
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_554-y,-x,-z-1/21
Buried area2770 Å2
ΔGint-23 kcal/mol
Surface area17050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.760, 120.760, 33.570
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Transcriptional regulatory repressor protein (TETR-family)


Mass: 25953.076 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Strain: H37Rv / Gene: ethR, MT3970, RV3855 / Production host: Escherichia coli (E. coli) / References: UniProt: P96222, UniProt: P9WMC1*PLUS
#2: Chemical ChemComp-3SF / 5,5,5-trifluoro-1-{4-[3-(1,3-thiazol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pentan-1-one


Mass: 374.381 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H17F3N4O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 2.36 Å3/Da / Density % sol: 47.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.7
Details: The crystallization buffer contained: 1.4 - 1.65M Ammonium Sulfate, 15% Glycerol and 0.1M MES pH6.7. , VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Dec 6, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.31→33.57 Å / Num. all: 11439 / Num. obs: 10878 / % possible obs: 95.09 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 3
Reflection shellResolution: 2.31→2.37 Å / % possible all: 99.7

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Processing

Software
NameVersionClassification
XDSdata scaling
MOLREPphasing
REFMAC5.5.0109refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1T56

1t56


Resolution: 2.31→32.34 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.881 / SU B: 7.377 / SU ML: 0.181 / Cross valid method: THROUGHOUT / ESU R Free: 0.241 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2739 547 4.8 %RANDOM
Rwork0.21775 ---
obs0.22043 10878 99.93 %-
all-10886 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.623 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20 Å20 Å2
2--0.07 Å20 Å2
3----0.14 Å2
Refinement stepCycle: LAST / Resolution: 2.31→32.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1500 0 25 3 1528
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0221558
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9191.9662125
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9525192
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.21823.61172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.63415239
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.721513
X-RAY DIFFRACTIONr_chiral_restr0.1160.2242
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211197
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.9521.5969
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.73621549
X-RAY DIFFRACTIONr_scbond_it2.8973589
X-RAY DIFFRACTIONr_scangle_it4.5954.5576
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.31→2.37 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.358 38 -
Rwork0.258 788 -
obs--99.88 %

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