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PDBsum entry 6fii
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Contents |
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438 a.a.
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424 a.a.
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123 a.a.
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349 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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A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.
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Authors
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G.Menchon,
A.E.Prota,
D.Lucena-Agell,
P.Bucher,
R.Jansen,
H.Irschik,
R.Müller,
I.Paterson,
J.F.Díaz,
K.H.Altmann,
M.O.Steinmetz.
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Ref.
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Nat Commun, 2018,
9,
2106.
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PubMed id
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Abstract
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Microtubule-targeting agents (MTAs) like taxol and vinblastine are among the
most successful chemotherapeutic drugs against cancer. Here, we describe a
fluorescence anisotropy-based assay that specifically probes for ligands
targeting the recently discovered maytansine site of tubulin. Using this assay,
we have determined the dissociation constants of known maytansine site ligands,
including the pharmacologically active degradation product of the clinical
antibody-drug conjugate trastuzumab emtansine. In addition, we discovered that
the two natural products spongistatin-1 and disorazole Z with established
cellular potency bind to the maytansine site on β-tubulin. The high-resolution
crystal structures of spongistatin-1 and disorazole Z in complex with tubulin
allowed the definition of an additional sub-site adjacent to the pocket shared
by all maytansine-site ligands, which could be exploitable as a distinct,
separate target site for small molecules. Our study provides a basis for the
discovery and development of next-generation MTAs for the treatment of cancer.
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