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PDBsum entry 2ync
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References listed in PDB file
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Key reference
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Title
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Validation of n-Myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach.
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Authors
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M.H.Wright,
B.Clough,
M.D.Rackham,
K.Rangachari,
J.A.Brannigan,
M.Grainger,
D.K.Moss,
A.R.Bottrill,
W.P.Heal,
M.Broncel,
R.A.Serwa,
D.Brady,
D.J.Mann,
R.J.Leatherbarrow,
R.Tewari,
A.J.Wilkinson,
A.A.Holder,
E.W.Tate.
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Ref.
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Nat Chem, 2014,
6,
112-121.
[DOI no: ]
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PubMed id
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Abstract
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Malaria is an infectious disease caused by parasites of the genus Plasmodium,
which leads to approximately one million deaths per annum worldwide. Chemical
validation of new antimalarial targets is urgently required in view of rising
resistance to current drugs. One such putative target is the enzyme
N-myristoyltransferase, which catalyses the attachment of the fatty acid
myristate to protein substrates (N-myristoylation). Here, we report an
integrated chemical biology approach to explore protein myristoylation in the
major human parasite P. falciparum, combining chemical proteomic tools for
identification of the myristoylated and glycosylphosphatidylinositol-anchored
proteome with selective small-molecule N-myristoyltransferase inhibitors. We
demonstrate that N-myristoyltransferase is an essential and chemically tractable
target in malaria parasites both in vitro and in vivo, and show that selective
inhibition of N-myristoylation leads to catastrophic and irreversible failure to
assemble the inner membrane complex, a critical subcellular organelle in the
parasite life cycle. Our studies provide the basis for the development of new
antimalarials targeting N-myristoyltransferase.
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