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PDBsum entry 3e6y
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Signaling protein
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PDB id
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3e6y
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References listed in PDB file
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Key reference
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Title
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A structural rationale for selective stabilization of anti-Tumor interactions of 14-3-3 proteins by cotylenin a.
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Authors
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C.Ottmann,
M.Weyand,
T.Sassa,
T.Inoue,
N.Kato,
A.Wittinghofer,
C.Oecking.
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Ref.
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J Mol Biol, 2009,
386,
913-919.
[DOI no: ]
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PubMed id
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Abstract
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Cotylenin A, a fungal metabolite originally described as a cytokinin-like
bioactive substance against plants shows differentiation-inducing and anti-tumor
activity in certain human cancers. Here, we present the crystal structure of
cotylenin A acting on a 14-3-3 regulatory protein complex. By comparison with
the closely related, but non-anticancer agent fusicoccin A, a rationale for the
activity of cotylenin A in human cancers is presented. This class of fusicoccane
diterpenoids are possible general modulators of 14-3-3 protein-protein
interactions. In this regard, specificities for individual 14-3-3/target protein
complexes might be achieved by varying the substituent pattern of the diterpene
ring system. As the different activities of fusicoccin A and cotylenin A in
human cancers suggest, hydroxylation of C12 might be a sufficient determinant of
structural specificity.
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Figure 1.
Fig. 1. Overall structure of dimeric tobacco 14-3-3 complexed
to cotylenin A and the H^+-ATPase phosphopeptide QSYpTV. (a)
Structure of cotylenin A. (b) Ribbon plot of the 14-3-3 dimer
(monomers colored sand and brown) binding two molecules of the
H^+-ATPase phosphopeptide (light blue sticks) and cotylenin A
(yellow sticks). Each monomer of the anti-parallel 14-3-3 dimer
comprises an amphipathic groove that accommodates the
phosphopeptide as well as the cotylenin A molecule.
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Figure 2.
Fig. 2. Binding of the H^+-ATPase phosphopeptide QSYpTV and
cotylenin A to the amphipathic groove of 14-3-3. (a) Cotylenin A
(yellow, sticks and semi-transparent surface) and the H^+-ATPase
phosphopeptide QSYpTV (light blue, sticks and semi-transparent
surface) are occupying the entire length of the amphipathic
groove of 14-3-3 (sand surface), the extreme C-terminal Val956
of the peptide displays a hydrophobic contact to the tricarbon
cycle of the cotylenin molecule. (b) Stereo view of the electron
density for cotylenin A bound to 14-3-3 and the C-terminal tail
of the H^+-ATPase peptide (QSYpTV-COOH). The peptide and
cotylenin A are drawn in ball-and-stick mode, 14-3-3 is
displayed as a ribbon (color coding as in a). An omit electron
density map of cotylenin A (contoured at 3 σ) is shown in
black. (c) Stereo view of a structural overlay of the position
of the diterpene molecules and the H^+-ATPase phosphopeptide in
the 14-3-3 complex structure with fusicoccin A (blue and
magenta, respectively, PDB code 1O9F) and with cotylenin A
(yellow and cyan, respectively).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2009,
386,
913-919)
copyright 2009.
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