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PDBsum entry 4o4l
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Cell cycle/inhibitor
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PDB id
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4o4l
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Contents |
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439 a.a.
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428 a.a.
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123 a.a.
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351 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural basis of microtubule stabilization by laulimalide and peloruside a.
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Authors
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A.E.Prota,
K.Bargsten,
P.T.Northcote,
M.Marsh,
K.H.Altmann,
J.H.Miller,
J.F.Díaz,
M.O.Steinmetz.
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Ref.
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Angew Chem Int Ed Engl, 2014,
53,
1621-1625.
[DOI no: ]
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PubMed id
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Abstract
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Laulimalide and peloruside A are microtubule-stabilizing agents (MSAs), the
mechanism of action on microtubules of which is poorly defined. Here, using
X-ray crystallography it is shown that laulimalide and peloruside A bind to a
unique non-taxane site on β-tubulin and use their respective macrolide core
structures to interact with a second tubulin dimer across protofilaments. At the
same time, they allosterically stabilize the taxane-site M-loop that establishes
lateral tubulin contacts in microtubules. Structures of ternary complexes of
tubulin with laulimalide/peloruside A and epothilone A are also solved, and
a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop
of β-tubulin is found. Together, the data define the mechanism of action of
laulimalide and peloruside A on tubulin and microtubules. The data further
provide a structural framework for understanding the synergy observed between
two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.
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