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PDBsum entry 2anl
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Hydrolase/hydrolase inhibitor
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PDB id
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2anl
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References listed in PDB file
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Key reference
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Title
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Structure of the aspartic protease plasmepsin 4 from the malarial parasite plasmodium malariae bound to an allophenylnorstatine-Based inhibitor.
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Authors
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J.C.Clemente,
L.Govindasamy,
A.Madabushi,
S.Z.Fisher,
R.E.Moose,
C.A.Yowell,
K.Hidaka,
T.Kimura,
Y.Hayashi,
Y.Kiso,
M.Agbandje-Mckenna,
J.B.Dame,
B.M.Dunn,
R.Mckenna.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2006,
62,
246-252.
[DOI no: ]
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PubMed id
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Abstract
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The malarial parasite continues to be one of the leading causes of death in many
developing countries. With the development of resistance to the currently
available treatments, the discovery of new therapeutics is imperative.
Currently, the plasmepsin enzymes found in the food vacuole of the parasite are
a chief target for drug development. Allophenylnorstatine-based compounds
originally designed to inhibit HIV-1 protease have shown efficacy against all
four plasmepsin enzymes found in the food vacuole of Plasmodium falciparum. In
this study, the first crystal structure of P. malariae plasmepsin 4 (PmPM4)
bound to the allophenylnorstatine-based compound KNI-764 is described at 3.3 A
resolution. The PmPM4-inhibitor complex crystallized in the orthorhombic space
group P2(1)2(1)2, with unit-cell parameters a = 95.9, b = 112.6, c = 90.4 A,
with two molecules in the asymmetric unit related by a non-crystallographic
symmetry operator. The structure was refined to a final R factor of 24.7%. The
complex showed the inhibitor in an unexpected binding orientation with
allophenylnorstatine occupying the S1' pocket. The P2 group was found outside
the S2 pocket, wedged between the flap and a juxtaposed loop. Inhibition
analysis of PmPM4 also suggests the potential for allophenylnorstatine-based
compounds to be effective against all species of malaria infecting humans and
for the future development of a broad-based inhibitor.
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Figure 3.
Figure 3 (a) Ribbon diagram of the PmPM4-KNI-764 complex. The
PmPM4  -strands,
coil and helices are colored yellow, green and red,
respectively. KNI-764 is depicted in green sticks. (b)
Structural superposition of the C^  trace
of PmPM4-KNI-764 (blue), PvPM4-pepstatin A (red; Bernstein et
al., 2003[Bernstein, N. K., Cherney, M. M., Yowell, C. A., Dame,
J. B. & James, M. N. (2003). J. Mol. Biol. 329, 505-524.]),
PfPM4-pepstatin A (green; Asojo et al., 2003[Asojo, O. A.,
Gulnik, S. V., Afonina, E., Yu, B., Ellman, J. A., Haque, T. S.
& Silva, A. M. (2003). J. Mol. Biol. 327, 173-181.]) and
PfPM2-Eh58 (orange; Asojo et al., 2003[Asojo, O. A., Gulnik, S.
V., Afonina, E., Yu, B., Ellman, J. A., Haque, T. S. & Silva, A.
M. (2003). J. Mol. Biol. 327, 173-181.]). This figure was
generated using PyMOL (DeLano, 2002[DeLano, W. L. (2002). The
PyMOL Molecular Graphics System. http://www.pymol.org .]).
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Figure 5.
Figure 5 Stereoviews of KNI-764 in the active site of PmPM4. (a)
View of P1 and P2 of KNI-764. (b) View of P1' and P2' of
KNI-764. The surface of the active site is shown as a beige
Connolly surface. PmPm4 is shown as a red ribbon. KNI-764 is
modeled as blue sticks. The residues of the flaps (Ile75-Val82)
and the 290s loop (Leu290-Glu295) are depicted as green sticks.
(c) Plausible hydrogen-bonding interactions (red broken lines)
between PmPM4 and KNI-764.
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2006,
62,
246-252)
copyright 2006.
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