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PDBsum entry 4uv6
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Cell invasion
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PDB id
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4uv6
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References listed in PDB file
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Key reference
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Title
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Crystal structure of plasmodium knowlesi apical membrane antigen 1 and its complex with an invasion-Inhibitory monoclonal antibody.
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Authors
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B.Vulliez-Le normand,
B.W.Faber,
F.A.Saul,
M.Van der eijk,
A.W.Thomas,
B.Singh,
C.H.Kocken,
G.A.Bentley.
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Ref.
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Plos One, 2015,
10,
e0123567.
[DOI no: ]
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PubMed id
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Abstract
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The malaria parasite Plasmodium knowlesi, previously associated only with
infection of macaques, is now known to infect humans as well and has become a
significant public health problem in Southeast Asia. This species should
therefore be targeted in vaccine and therapeutic strategies against human
malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium
merozoite invasion of the erythrocyte, is currently being pursued in human
vaccine trials against P. falciparum. Recent vaccine trials in macaques using
the P. knowlesi orthologue PkAMA1 have shown that it protects against infection
by this parasite species and thus should be developed for human vaccination as
well. Here, we present the crystal structure of Domains 1 and 2 of the PkAMA1
ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody
R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck
Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2
inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric
blocking of the hydrophobic groove and by preventing the displacement of the D2
loop which is essential for exposing the complete binding site on AMA1. R31C2
recognizes a non-polymorphic epitope and should thus be cross-strain reactive.
PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues.
Unlike these two latter species, there are no polymorphic sites close to the
RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a
mechanism of immune escape from the host's humoral response to AMA1.
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