Journal
EMBO REPORTS
Volume 9, Issue 11, Pages 1101-1106Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/embor.2008.171
Keywords
antimitotics; GTPase; microtubules; nucleotide exchange; structure
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Funding
- Centre National de la Recherche Scientifique, La Ligue Contre Le Cancer (equipe labellisee 2006)
- l'Agence Nationale de la Recherche [ANR-05-BLAN-0292]
- Agence Nationale de la Recherche (ANR) [ANR-05-BLAN-0292] Funding Source: Agence Nationale de la Recherche (ANR)
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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 beta-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.
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