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PDBsum entry 4m3f
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Transcription repressor/inhibitor
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PDB id
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4m3f
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PDB id:
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| Name: |
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Transcription repressor/inhibitor
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Title:
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Rapid and efficient design of new inhibitors of mycobacterium tuberculosis transcriptional repressor ethr using fragment growing, merging and linking approaches
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Structure:
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Hth-type transcriptional regulator ethr. Chain: a. Synonym: transcriptional regulatory repressor protein (tetr-family). Engineered: yes
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Source:
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Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: h37rv. Gene: etar, ethr, mt3970, rv3855. Expressed in: escherichia coli. Expression_system_taxid: 511693.
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Resolution:
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2.00Å
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R-factor:
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0.237
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R-free:
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0.285
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Authors:
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B.Villemagne,M.Flipo,N.Blondiaux,C.Crauste,S.Malaquin,F.Leroux, C.Piveteau,V.Villeret,P.Brodin,B.Villoutreix,O.Sperandio, A.Wohlkonig,R.Wintjens,B.Deprez,A.Baulard,N.Willand
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Key ref:
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B.Villemagne
et al.
(2014).
Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches.
J Med Chem,
57,
4876-4888.
PubMed id:
DOI:
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Date:
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06-Aug-13
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Release date:
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25-Jun-14
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PROCHECK
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Headers
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References
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P9WMC1
(ETHR_MYCTU) -
HTH-type transcriptional regulator EthR from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
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Seq:
Struc:
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216 a.a.
193 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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J Med Chem
57:4876-4888
(2014)
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PubMed id:
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Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches.
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B.Villemagne,
M.Flipo,
N.Blondiaux,
C.Crauste,
S.Malaquin,
F.Leroux,
C.Piveteau,
V.Villeret,
P.Brodin,
B.O.Villoutreix,
O.Sperandio,
S.H.Soror,
A.Wohlkönig,
R.Wintjens,
B.Deprez,
A.R.Baulard,
N.Willand.
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ABSTRACT
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Tuberculosis remains a major cause of mortality and morbidity, killing each year
more than one million people. Although the combined use of first line
antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient
to treat most patients, the rapid emergence of multidrug resistant strains of
Mycobacterium tuberculosis stresses the need for alternative therapies.
Mycobacterial transcriptional repressor EthR is a key player in the control of
second-line drugs bioactivation such as ethionamide and has been shown to impair
the sensitivity of the human pathogen Mycobacterium tuberculosis to this
antibiotic. As a way to identify new potent ligands of this protein, we have
developed fragment-based approaches. In the current study, we combined surface
plasmon resonance assay, X-ray crystallography, and ligand efficiency driven
design for the rapid discovery and optimization of new chemotypes of EthR
ligands starting from a fragment. The design, synthesis, and in vitro and ex
vivo activities of these compounds will be discussed.
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Links
