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- PDB-4m3e: Rapid and efficient design of new inhibitors of Mycobacterium tub... -

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Basic information

Entry
Database: PDB / ID: 4m3e
TitleRapid and efficient design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging and linking approaches
ComponentsHTH-type transcriptional regulator EthR
KeywordsTRANSCRIPTION REPRESSOR/INHIBITOR / helix-turn-helix DNA binding protein / TETR-family / transcriptional regulatory repressor / inhibitor / 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-2B3 / HTH-type transcriptional regulator EthR / HTH-type transcriptional regulator EthR
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.109 Å
AuthorsVillemagne, B. / Flipo, M. / Blondiaux, N. / Crauste, C. / Malaquin, S. / Leroux, F. / Piveteau, C. / Villeret, V. / Brodin, P. / Villoutreix, B. ...Villemagne, B. / Flipo, M. / Blondiaux, N. / Crauste, C. / Malaquin, S. / Leroux, F. / Piveteau, C. / Villeret, V. / Brodin, P. / Villoutreix, B. / Sperandio, O. / Wohlkonig, A. / Wintjens, R. / Deprez, B. / Baulard, A. / Willand, N.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches.
Authors: Villemagne, B. / Flipo, M. / Blondiaux, N. / Crauste, C. / Malaquin, S. / Leroux, F. / Piveteau, C. / Villeret, V. / Brodin, P. / Villoutreix, B.O. / Sperandio, O. / Soror, S.H. / Wohlkonig, ...Authors: Villemagne, B. / Flipo, M. / Blondiaux, N. / Crauste, C. / Malaquin, S. / Leroux, F. / Piveteau, C. / Villeret, V. / Brodin, P. / Villoutreix, B.O. / Sperandio, O. / Soror, S.H. / Wohlkonig, A. / Wintjens, R. / Deprez, B. / Baulard, A.R. / Willand, N.
History
DepositionAug 6, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

Deposited unit
A: HTH-type transcriptional regulator EthR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2172
Polymers23,7821
Non-polymers4351
Water905
1
A: HTH-type transcriptional regulator EthR
hetero molecules

A: HTH-type transcriptional regulator EthR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4344
Polymers47,5632
Non-polymers8712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_554-y,-x,-z-1/21
Buried area2760 Å2
ΔGint-22 kcal/mol
Surface area17350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.058, 122.058, 33.836
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein HTH-type transcriptional regulator EthR / transcriptional regulatory repressor protein (TETR-family)


Mass: 23781.705 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Strain: H37RV / Gene: etaR, ethR, MT3970, Rv3855 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P96222, UniProt: P9WMC1*PLUS
#2: Chemical ChemComp-2B3 / 4-(2-{[(propylsulfonyl)amino]methyl}-1,3-thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzamide


Mass: 435.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20F3N3O3S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.65 Å3/Da / Density % sol: 53.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.7
Details: 1.4-1.65 M ammonium sulfate, 15% glycerol, 0.1 M MES, pH 6.7, 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 225 mm CCD / Detector: CCD / Date: Feb 10, 2011
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.109→38.598 Å / Num. all: 14939 / Num. obs: 14939 / % possible obs: 97.6 % / Redundancy: 5.9 % / Rsym value: 0.175 / Net I/σ(I): 7.7
Reflection shell

Rmerge(I) obs: 0.014 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.109-2.223.30.6624719131.42189.1
2.22-2.364.20.8825219711.04196.8
2.36-2.5251963019190.75798.6
2.52-2.7261.51091718110.51699.1
2.72-2.986.921175516930.3899.7
2.98-3.337.53.21164715530.239100
3.33-3.857.65.71046913760.132100
3.85-4.717.38.4862011790.08799.9
4.71-6.677.3969209540.08100
6.67-38.5986.616.237465700.03799.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.3 Å38.6 Å
Translation2.3 Å38.6 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
MAR345dtbdata collection
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.109→38.598 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.843 / WRfactor Rfree: 0.2662 / WRfactor Rwork: 0.2132 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7619 / SU B: 8.182 / SU ML: 0.203 / SU R Cruickshank DPI: 0.2363 / SU Rfree: 0.2172 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.236 / ESU R Free: 0.217 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.3077 755 5.1 %RANDOM
Rwork0.252 ---
obs0.2548 14912 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 61.85 Å2 / Biso mean: 26.9555 Å2 / Biso min: 4.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2--0.01 Å20 Å2
3----0.03 Å2
Refinement stepCycle: LAST / Resolution: 2.109→38.598 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1500 0 28 5 1533
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0221560
X-RAY DIFFRACTIONr_angle_refined_deg1.7651.9672128
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7575192
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.30723.61172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.27415239
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0541513
X-RAY DIFFRACTIONr_chiral_restr0.1150.2242
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211195
X-RAY DIFFRACTIONr_mcbond_it0.8521.5961
X-RAY DIFFRACTIONr_mcangle_it1.48821543
X-RAY DIFFRACTIONr_scbond_it2.5683599
X-RAY DIFFRACTIONr_scangle_it4.2684.5585
LS refinement shellResolution: 2.109→2.163 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.45 56 -
Rwork0.395 808 -
all-864 -
obs--100 %

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