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  • Title: Structure of 4'-demethylepipodophyllotoxin in complex with tubulin provides a rationale for drug design.
    Author: Niu L, Wang Y, Wang C, Wang Y, Jiang X, Ma L, Wu C, Yu Y, Chen Q.
    Journal: Biochem Biophys Res Commun; 2017 Nov 04; 493(1):718-722. PubMed ID: 28864414.
    Abstract:
    Microtubules consists of αβ-tubulin heterodimers and are highly attractive targets for anti-cancer drugs. A broad range of agents have been identified to bind to tubulin and interfere with microtubule assembly, including colchicine binding site inhibitors (CBSIs). Podophyllotoxin is a CBSI that inhibits the assembly of microtubules. However, for a long time, the design and development of podophyllotoxin family drugs have been hindered by the lack of high-resolution structural information of the tubulin-agent complex. We report the first high-resolution (2.8 Å) structure of a podophyllotoxin family agent (4'-demethylepipodophyllotoxin, DMEP) complexed with tubulin and revealed the detailed interactions between DMEP and tubulin. Comparison of this structure and other CBSIs explains previous results of the structure-activity-relationship (SAR) studies, and provides insights into the development of new podophyllotoxin derivatives targeting the colchicine site.
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