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Structural insight into the inhibition of tubulin by vinca domain peptide ligands
Author(s) -
Cormier Anthony,
Marchand Matthieu,
Ravelli Raimond B G,
Knossow Marcel,
Gigant Benoît
Publication year - 2008
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2008.171
Subject(s) - vinca , tubulin , microtubule , stathmin , vinblastine , gtp' , biology , microbiology and biotechnology , vinca alkaloid , calmodulin , biochemistry , stereochemistry , chemistry , enzyme , genetics , pharmacology , chemotherapy , vincristine , cyclophosphamide
The tubulin vinca domain is the target of widely different microtubule inhibitors that interfere with the binding of vinblastine. Although all these ligands inhibit the hydrolysis of GTP, they affect nucleotide exchange to variable extents. The structures of two vinca domain antimitotic peptides—phomopsin A and soblidotin (a dolastatin 10 analogue)—bound to tubulin in a complex with a stathmin‐like domain show that their sites partly overlap with that of vinblastine and extend the definition of the vinca domain. The structural data, together with the biochemical results from the ligands we studied, highlight two main contributors in nucleotide exchange: the flexibility of the tubulin subunits' arrangement at their interfaces and the residues in the carboxy‐terminal part of the β‐tubulin H6–H7 loop. The structures also highlight common features of the mechanisms by which vinca domain ligands favour curved tubulin assemblies and destabilize microtubules.