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PDBsum entry 4yga
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Metal binding protein
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PDB id
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4yga
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References listed in PDB file
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Key reference
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Title
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Allosteric activation of apicomplexan calcium-Dependent protein kinases.
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Authors
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J.R.Ingram,
K.E.Knockenhauer,
B.M.Markus,
J.Mandelbaum,
A.Ramek,
Y.Shan,
D.E.Shaw,
T.U.Schwartz,
H.L.Ploegh,
S.Lourido.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
E4975.
[DOI no: ]
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PubMed id
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Abstract
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Calcium-dependent protein kinases (CDPKs) comprise the major group of
Ca(2+)-regulated kinases in plants and protists. It has long been assumed that
CDPKs are activated, like other Ca(2+)-regulated kinases, by derepression of the
kinase domain (KD). However, we found that removal of the autoinhibitory domain
from Toxoplasma gondii CDPK1 is not sufficient for kinase activation. From a
library of heavy chain-only antibody fragments (VHHs), we isolated an antibody
(1B7) that binds TgCDPK1 in a conformation-dependent manner and potently
inhibits it. We uncovered the molecular basis for this inhibition by solving the
crystal structure of the complex and simulating, through molecular dynamics, the
effects of 1B7-kinase interactions. In contrast to other Ca(2+)-regulated
kinases, the regulatory domain of TgCDPK1 plays a dual role, inhibiting or
activating the kinase in response to changes in Ca(2+) concentrations. We
propose that the regulatory domain of TgCDPK1 acts as a molecular splint to
stabilize the otherwise inactive KD. This dependence on allosteric stabilization
reveals a novel susceptibility in this important class of parasite enzymes.
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