Document Detail


Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents.
MedLine Citation:
PMID:  23287720     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. Here, we determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane-pocket of β-tubulin and used their respective side chain to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. They further offer fundamental structural insights into the control mechanisms of microtubule dynamics.
Authors:
Andrea E Prota; Katja Bargsten; Didier Zurwerra; Jessica J Field; José Fernando Díaz; Karl-Heinz Altmann; Michel O Steinmetz
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-3
Journal Detail:
Title:  Science (New York, N.Y.)     Volume:  -     ISSN:  1095-9203     ISO Abbreviation:  Science     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0404511     Medline TA:  Science     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland.
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