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PDBsum entry 7daf
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Contents |
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442 a.a.
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423 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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High-Resolution X-Ray structure of three microtubule-Stabilizing agents in complex with tubulin provide a rationale for drug design.
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Authors
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Q.Xiao,
T.Xue,
W.Shuai,
C.Wu,
Z.Zhang,
T.Zhang,
S.Zeng,
B.Sun,
Y.Wang.
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Ref.
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Biochem Biophys Res Commun, 2021,
534,
330-336.
[DOI no: ]
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PubMed id
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Abstract
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Microtubule is a key component of cytoskeleton and has been considered as an
important target for the treatment of cancer. In particular, the tubulin
taxane-site inhibitors such as taxol analogs and epothilones have achieved great
success in clinical trials. However, the structural basis of many taxane-site
inhibitors is still lacking in exploring their mechanism of action. We here
reported crystal complex structures for three taxane-site inhibitors,
Ixabepilone, Epothilone B, and Epothilone D, which were determined to 2.4 Å,
2.4 Å, and 2.85 Å, respectively. The crystal structures revealed that these
taxane-site inhibitors possess similar binding modes to that of Epothilone A at
the taxane site, e.g. making critical hydrogen-bonding interactions with
multiple residues on the M-loop, which facilitating the tubulin polymerization.
Furthermore, we summarized the binding modes of almost all taxane-site
inhibitors and identified novel taxane-site ligands with simpler chemical
structures through virtual screening. On this basis, new derivatives with higher
binding affinity to tubulin were designed and developed, which can form
additional hydrogen bond interactions with tubulin. Overall, this work
determined the mechanism of action of epothilones and provided a structural
basis to design reasonably novel taxane-site inhibitors with simpler structure
and improved pharmacokinetic properties.
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