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PDBsum entry 4zol
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Structural protein/inhibitor
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PDB id
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4zol
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Contents |
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439 a.a.
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430 a.a.
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122 a.a.
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348 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 insights into the pharmacophore of vinca domain inhibitors of microtubules.
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Authors
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Y.Wang,
F.W.Benz,
Y.Wu,
Q.Wang,
Y.Chen,
X.Chen,
H.Li,
Y.Zhang,
R.Zhang,
J.Yang.
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Ref.
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Mol Pharmacol, 2016,
89,
233-242.
[DOI no: ]
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PubMed id
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Abstract
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Antibody-drug conjugates (ADCs) have achieved great success in cancer therapy in
recent years. Some peptidyl microtubule inhibitors consisting of natural and
unnatural amino acids, such as monomethyl auristatin E (MMAE) and F (MMAF), are
extremely cytotoxic and have been used as a payload in ADCs. However, their
precise molecular interaction with tubulin and microtubules remains unclear. We
determined the crystal structures of tubulin in complex with three ultra-potent
peptidyl microtubule inhibitors [MMAE, taltobulin (HTI- 286), and tubulysin M]
at 2.5 Å. Our data showed that the three peptides bound to the vinca domain and
shared a common and key pharmacophore containing two consecutive hydrophobic
groups (Val, Ile-like side chain). These groups protruded in opposite directions
into hydrophobic pockets on the tubulin β and α subunits. Nitrogen and oxygen
atoms from the same backbone formed hydrogen bonds with Asn329 from the α
subunit and Asp179 from the β subunit in a direction normal to the surface
formed by the aforementioned hydrophobic groups. In addition, our crystal
structure data indicated that tubulysin M bound to the β subunit alone,
providing a structural explanation for its higher affinity. We also compared the
conformations of two representative structurally different vinca domain
compounds, ustiloxin D and vinblastine, with those of the aforementioned
peptidyl ligands, and found that they shared a similar pharmacophore. Our
findings lay a foundation for the rational design of novel vinca domain ligands
and may facilitate the development of microtubule inhibitors with high
specificity, affinity, and efficiency as payloads for ADCs in cancer therapy.
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