 |
PDBsum entry 4zil
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
4zil
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The redox state regulates the conformation of rv2466c to activate the antitubercular prodrug tp053.
|
|
|
Authors
|
|
D.Albesa-Jové,
N.Comino,
M.Tersa,
E.Mohorko,
S.Urresti,
E.Dainese,
L.R.Chiarelli,
M.R.Pasca,
R.Manganelli,
V.Makarov,
G.Riccardi,
D.I.Svergun,
R.Glockshuber,
M.E.Guerin.
|
|
|
Ref.
|
|
J Biol Chem, 2015,
290,
31077-31089.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Rv2466c is a key oxidoreductase that mediates the reductive activation of TP053,
a thienopyrimidine derivative that kills replicating and non-replicating
Mycobacterium tuberculosis, but whose mode of action remains enigmatic. Rv2466c
is a homodimer in which each subunit displays a modular architecture comprising
a canonical thioredoxin-fold with a Cys(19)-Pro(20)-Trp(21)-Cys(22) motif, and
an insertion consisting of a four α-helical bundle and a short α-helical
hairpin. Strong evidence is provided for dramatic conformational changes during
the Rv2466c redox cycle, which are essential for TP053 activity. Strikingly, a
new crystal structure of the reduced form of Rv2466c revealed the binding of a
C-terminal extension in α-helical conformation to a pocket next to the active
site cysteine pair at the interface between the thioredoxin domain and the
helical insertion domain. The ab initio low-resolution envelopes obtained from
small angle x-ray scattering showed that the fully reduced form of Rv2466c
adopts a "closed" compact conformation in solution, similar to that
observed in the crystal structure. In contrast, the oxidized form of Rv2466c
displays an "open" conformation, where tertiary structural changes in
the α-helical subdomain suffice to account for the observed conformational
transitions. Altogether our structural, biochemical, and biophysical data
strongly support a model in which the formation of the catalytic disulfide bond
upon TP053 reduction triggers local structural changes that open the substrate
binding site of Rv2466c allowing the release of the activated, reduced form of
TP053. Our studies suggest that similar structural changes might have a
functional role in other members of the thioredoxin-fold superfamily.
|
|
|
|
|
|
|
