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PDBsum entry 3i7c
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References listed in PDB file
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Key reference
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Title
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Toxoplasma gondii calcium-Dependent protein kinase 1 is a target for selective kinase inhibitors.
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Authors
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K.K.Ojo,
E.T.Larson,
K.R.Keyloun,
L.J.Castaneda,
A.E.Derocher,
K.K.Inampudi,
J.E.Kim,
T.L.Arakaki,
R.C.Murphy,
L.Zhang,
A.J.Napuli,
D.J.Maly,
C.L.Verlinde,
F.S.Buckner,
M.Parsons,
W.G.Hol,
E.A.Merritt,
W.C.Van voorhis.
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Ref.
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Nat Struct Biol, 2010,
17,
602-607.
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PubMed id
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Abstract
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New drugs are needed to treat toxoplasmosis. Toxoplasma gondii calcium-dependent
protein kinases (TgCDPKs) are attractive targets because they are absent in
mammals. We show that TgCDPK1 is inhibited by low nanomolar levels of bumped
kinase inhibitors (BKIs), compounds inactive against mammalian kinases.
Cocrystal structures of TgCDPK1 with BKIs confirm that the structural basis for
selectivity is due to the unique glycine gatekeeper residue in the ATP-binding
site. We show that BKIs interfere with an early step in T. gondii infection of
human cells in culture. Furthermore, we show that TgCDPK1 is the in vivo target
of BKIs because T. gondii expressing a glycine to methionine gatekeeper mutant
enzyme show significantly decreased sensitivity to BKIs. Thus, design of
selective TgCDPK1 inhibitors with low host toxicity may be achievable.
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