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PDBsum entry 3g1m
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Transcription
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PDB id
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3g1m
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Contents |
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* Residue conservation analysis
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PDB id:
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Transcription
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Title:
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Ethr from mycobacterium tuberculosis in complex with compound bdm31381
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Structure:
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Transcriptional regulatory repressor protein (tetr-family) ethr. Chain: a. Synonym: transcriptional regulator, tetr family. Engineered: yes
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Source:
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Mycobacterium tuberculosis. Organism_taxid: 1773. Strain: h37rv. Gene: ethr, mt3970, rv3855. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.70Å
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R-factor:
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0.183
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R-free:
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0.213
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Authors:
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N.Willand,B.Dirie,X.Carette,P.Bifani,A.Singhal,M.Desroses,F.Leroux, E.Willery,V.Mathys,R.Deprez-Poulain,G.Delcroix,F.Frenois, M.Aumercier,C.Locht,V.Villeret,B.Deprez,A.R.Baulard
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Key ref:
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N.Willand
et al.
(2009).
Synthetic EthR inhibitors boost antituberculous activity of ethionamide.
Nat Med,
15,
537-544.
PubMed id:
DOI:
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Date:
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30-Jan-09
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Release date:
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21-Jul-09
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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.
194 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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Nat Med
15:537-544
(2009)
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PubMed id:
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Synthetic EthR inhibitors boost antituberculous activity of ethionamide.
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N.Willand,
B.Dirié,
X.Carette,
P.Bifani,
A.Singhal,
M.Desroses,
F.Leroux,
E.Willery,
V.Mathys,
R.Déprez-Poulain,
G.Delcroix,
F.Frénois,
M.Aumercier,
C.Locht,
V.Villeret,
B.Déprez,
A.R.Baulard.
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ABSTRACT
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The side effects associated with tuberculosis therapy bring with them the risk
of noncompliance and subsequent drug resistance. Increasing the therapeutic
index of antituberculosis drugs should thus improve treatment effectiveness.
Several antituberculosis compounds require in situ metabolic activation to
become inhibitory. Various thiocarbamide-containing drugs, including
ethionamide, are activated by the mycobacterial monooxygenase EthA, the
production of which is controlled by the transcriptional repressor EthR. Here we
identify drug-like inhibitors of EthR that boost the bioactivation of
ethionamide. Compounds designed and screened for their capacity to inhibit
EthR-DNA interaction were co-crystallized with EthR. We exploited the
three-dimensional structures of the complexes for the synthesis of improved
analogs that boosted the ethionamide potency in culture more than tenfold. In
Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343,
enabled a substantially reduced dose of ethionamide to lessen the mycobacterial
load as efficiently as the conventional higher-dose treatment. This provides
proof of concept that inhibiting EthR improves the therapeutic index of
thiocarbamide derivatives, which should prompt reconsideration of their use as
first-line drugs.
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Selected figure(s)
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Figure 4.
The formation of the hydrogen bond between Asn179 and the
oxygen atom of the carbonyl function of BDM31381 is illustrated
by the dotted pink line.
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Figure 5.
All of the structures obtained belong to space group
P4[1]2[1]2, which allows for objective comparison and
measurements.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Med
(2009,
15,
537-544)
copyright 2009.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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S.Ekins,
J.S.Freundlich,
I.Choi,
M.Sarker,
and
C.Talcott
(2011).
Computational databases, pathway and cheminformatics tools for tuberculosis drug discovery.
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Trends Microbiol,
19,
65-74.
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H.Wade
(2010).
MD recognition by MDR gene regulators.
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Curr Opin Struct Biol,
20,
489-496.
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N.Dhar,
and
J.D.McKinney
(2010).
Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice.
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Proc Natl Acad Sci U S A,
107,
12275-12280.
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S.Ekins,
T.Kaneko,
C.A.Lipinski,
J.Bradford,
K.Dole,
A.Spektor,
K.Gregory,
D.Blondeau,
S.Ernst,
J.Yang,
N.Goncharoff,
M.M.Hohman,
and
B.A.Bunin
(2010).
Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis.
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Mol Biosyst,
6,
2316-2324.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
