 |
PDBsum entry 2o2y
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
2o2y
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Studies of toxoplasma gondii and plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents.
|
|
|
Authors
|
|
S.P.Muench,
S.T.Prigge,
R.Mcleod,
J.B.Rafferty,
M.J.Kirisits,
C.W.Roberts,
E.J.Mui,
D.W.Rice.
|
|
|
Ref.
|
|
Acta Crystallogr D Biol Crystallogr, 2007,
63,
328-338.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Recent studies have demonstrated that submicromolar concentrations of the
biocide triclosan arrest the growth of the apicomplexan parasites Plasmodium
falciparum and Toxoplasma gondii and inhibit the activity of the apicomplexan
enoyl acyl carrier protein reductase (ENR). The crystal structures of T. gondii
and P. falciparum ENR in complex with NAD(+) and triclosan and of T. gondii ENR
in an apo form have been solved to 2.6, 2.2 and 2.8 A, respectively. The
structures of T. gondii ENR have revealed that, as in its bacterial and plant
homologues, a loop region which flanks the active site becomes ordered upon
inhibitor binding, resulting in the slow tight binding of triclosan. In
addition, the T. gondii ENR-triclosan complex reveals the folding of a
hydrophilic insert common to the apicomplexan family that flanks the
substrate-binding domain and is disordered in all other reported apicomplexan
ENR structures. Structural comparison of the apicomplexan ENR structures with
their bacterial and plant counterparts has revealed that although the active
sites of the parasite enzymes are broadly similar to those of their bacterial
counterparts, there are a number of important differences within the
drug-binding pocket that reduce the packing interactions formed with several
inhibitors in the apicomplexan ENR enzymes. Together with other significant
structural differences, this provides a possible explanation of the lower
affinity of the parasite ENR enzyme family for aminopyridine-based inhibitors,
suggesting that an effective antiparasitic agent may well be distinct from
equivalent antimicrobials.
|
|
|
|
|
|
|
|
Figure 1.
Figure 1 The structural formulae of (a) triclosan and (b)
(E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ylacrylamide
(compound 29) produced using the program ISIS/Draw.
|
|
Figure 4.
Figure 4 2F[obs] - 1F[calc] electron-density maps for (a) PfENR
and (b) TgENR contoured at 0.8  produced
after initial rigid-body refinement in REFMAC5 (Murshudov et
al., 1997[Murshudov, G., Vagin, A. & Dodson, E. (1997). Acta
Cryst. D53, 240-255.]). Both NAD^+ and triclosan were omitted
from the model during refinement, but are represented in stick
format in order to show their unambiguous position in the
initial electron-density maps. (c) Stereo diagram of the
residues responsible for forming a hydrogen-bonding network to
the NAD^+ cofactor in subunit A of TgENR. (d) Stereo diagram of
the triclosan-binding site of subunit A of TgENR, with the
active-site residues Tyr179, Tyr189, Lys197 and Phe243 labelled.
(c) and (d) use the colour scheme yellow, red, blue, green and
orange for carbon, oxygen, nitrogen, chlorine and phosphorus,
respectively, and were produced in TURBO-FRODO (Roussel et al.,
1990[Roussel, A., Fontecilla-Camps, J. C. & Cambillau, C.
(1990). Acta Cryst. A46, C66-C67.]).
|
|
|
|
|
|
The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2007,
63,
328-338)
copyright 2007.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Expression, Purification and crystallization of the plasmodium falciparum enoyl reductase.
|
|
|
Authors
|
|
S.P.Muench,
J.B.Rafferty,
R.Mcleod,
D.W.Rice,
S.T.Prigge.
|
|
|
Ref.
|
|
Acta Crystallogr D Biol Crystallogr, 2003,
59,
1246-1248.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
Figure 2.
Figure 2 A representative 1° oscillation image of data
collected from a crystal of pfENR complexed with NAD^+ and
triclosan on a Quantum Q4 CCD detector on station 14.1 at the
SRS Daresbury Laboratory. The resolution at the edge of the
image corresponds to a resolution of 2.2 Å.
|
|
|
|
|
|
The above figure is
reproduced from the cited reference
with permission from the IUCr
|
|
|
|
|
|
|
