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PDBsum entry 1lf3
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Novel uncomplexed and complexed structures of plasmepsin ii, An aspartic protease from plasmodium falciparum.
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Authors
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O.A.Asojo,
S.V.Gulnik,
E.Afonina,
B.Yu,
J.A.Ellman,
T.S.Haque,
A.M.Silva.
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Ref.
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J Mol Biol, 2003,
327,
173-181.
[DOI no: ]
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PubMed id
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Abstract
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Malaria remains a human disease of global significance and a major cause of high
infant mortality in endemic nations. Parasites of the genus Plasmodium cause the
disease by degrading human hemoglobin as a source of amino acids for their
growth and maturation. Hemoglobin degradation is initiated by aspartic
proteases, termed plasmepsins, with a cleavage at the alpha-chain between
residues Phe33 and Leu34. Plasmepsin II is one of the four catalytically active
plasmepsins that has been identified in the food vacuole of Plasmodium
falciparum. Novel crystal structures of uncomplexed plasmepsin II as well as the
complex with a potent inhibitor have been refined with data extending to
resolution limits of 1.9A and 2.7A, and to R factors of 17% and 18%,
respectively. The inhibitor,
N-(3-[(2-benzo[1,3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl)-propionyl]-amino]-1-benzyl-2-(hydroxypropyl)-4-benzyloxy-3,5-dimethoxy-benzamide,
belongs to a family of potent non-peptidic inhibitors that have large P1'
groups. Such inhibitors could not be modeled into the binding cavity of the
structure of plasmepsin II in complex with pepstatin A. Our structures reveal
that the binding cavities of the new complex and uncomplexed plasmepsin II are
considerably more open than that of the pepstatin A complex, allowing for larger
heterocyclic groups in the P1', P2' and P2 positions. Both complexed and
uncomplexed plasmepsin II crystallized in space group P2, with one monomer in
the asymmetric unit. The structures show extensive interlocking of monomers
around the crystallographic axis of symmetry, with areas in excess of 2300A(2)
buried at the interface, and a loop of one monomer interacting with the binding
cavity of the 2-fold related monomer. Electron density for this loop is only
fully ordered in the complexed structure.
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Figure 1.
Figure 1. Ribbon diagram of the complex of plasmepsin II
with EH58 showing disulfide bridges, catalytic dyad, inhibitor,
flap, flexible loop and proline-rich loop in red, magenta,
white, blue, yellow and green, respectively.
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Figure 4.
Figure 4. Surface representations of a monomer of (a)
uncomplexed Plm II and Plm II in complex with (b) EH58 and (c)
pepstatin A, with the binding cavity of the complex with
pepstatin A revealing a much tighter embrace of the inhibitor.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2003,
327,
173-181)
copyright 2003.
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