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- PDB-4m3g: Rapid and efficient design of new inhibitors of Mycobacterium tub... -

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Basic information

Entry
Database: PDB / ID: 4m3g
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 / Homeobox-like domain superfamily ...: / 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-2G1 / 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: 2.3 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)24,1322
Polymers23,7821
Non-polymers3501
Water21612
1
A: HTH-type transcriptional regulator EthR
hetero molecules

A: HTH-type transcriptional regulator EthR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,2644
Polymers47,5632
Non-polymers7012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area2870 Å2
ΔGint-21 kcal/mol
Surface area17240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.850, 121.850, 34.154
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-2G1 / 4-(2-methyl-1,3-thiazol-4-yl)-N-(3,3,3-trifluoropropyl)benzenesulfonamide


Mass: 350.380 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H13F3N2O2S2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.67 Å3/Da / Density % sol: 53.85 %
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: Oct 24, 2011
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.202→40.617 Å / Num. all: 13616 / Num. obs: 13616 / % possible obs: 99.7 % / Redundancy: 7.7 % / Rsym value: 0.124 / Net I/σ(I): 14.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.202-2.327.60.9320.81447019070.93298.1
2.32-2.467.80.6311.21448418460.631100
2.46-2.637.90.4261.91377817440.426100
2.63-2.847.90.3142.51276616240.314100
2.84-3.117.90.2043.91177014990.204100
3.11-3.487.80.1196.61057713620.119100
3.48-4.027.60.0692.2926212170.069100
4.02-4.927.60.03918.9806910670.039100
4.92-6.967.40.04317.561618380.043100
6.96-40.6176.50.01835.433175120.01899.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.58 Å38.53 Å
Translation2.58 Å38.53 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
MAR345dtbdata collection
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→38.53 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.922 / WRfactor Rfree: 0.2048 / WRfactor Rwork: 0.1733 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8579 / SU B: 5.821 / SU ML: 0.144 / SU R Cruickshank DPI: 0.252 / SU Rfree: 0.2059 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.252 / ESU R Free: 0.206 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2402 566 4.8 %RANDOM
Rwork0.2002 ---
obs0.2022 11907 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: 76.23 Å2 / Biso mean: 34.1495 Å2 / Biso min: 10.51 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.3→38.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1487 0 22 12 1521
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0221540
X-RAY DIFFRACTIONr_angle_refined_deg1.8111.9642100
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0195189
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3823.52171
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.19715238
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3241513
X-RAY DIFFRACTIONr_chiral_restr0.1240.2238
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211177
X-RAY DIFFRACTIONr_mcbond_it1.0771.5950
X-RAY DIFFRACTIONr_mcangle_it1.99221525
X-RAY DIFFRACTIONr_scbond_it3.4383590
X-RAY DIFFRACTIONr_scangle_it5.3974.5575
LS refinement shellResolution: 2.3→2.362 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.268 44 -
Rwork0.217 776 -
all-820 -
obs--100 %

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