Structural Basis of Microtubule Stabilization by Discodermolide

• Published in: Chembiochem : a European journal of chemical biology 2017-05, Vol.18 (10), p.905-909
• Main Authors: Prota, Andrea E., Bargsten, Katja, Redondo‐Horcajo, Mariano, Smith, Amos B., Yang, Chia‐Ping H., McDaid, Hayley M., Paterson, Ian, Horwitz, Susan B., Fernando Díaz, José, Steinmetz, Michel O.
• Format: Article
• Language: English
• Subjects: Alkanes - chemistry; Alkanes - metabolism; Binding; Binding Sites; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - metabolism; Carbamates - chemistry; Carbamates - metabolism; Chemotherapy; Conformation; Crystallography; Crystallography, X-Ray; drug design; Helices; Humans; Lactones - chemistry; Lactones - metabolism; microtubules; Microtubules - metabolism; molecular mechanism of action; Paclitaxel; Pyrones - chemistry; Pyrones - metabolism; Stabilizers (agents); structure elucidation; Taxoids - chemistry; Taxoids - metabolism; Tubulin; Tubulin - chemistry; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - metabolism; X-ray crystallography
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201600696

Microtubule‐stabilizing agents (MSAs) are widely used in chemotherapy. Using X‐ray crystallography we elucidated the detailed binding modes of two potent MSAs, (+)‐discodermolide (DDM) and the DDM–paclitaxel hybrid KS‐1‐199‐32, in the taxane pocket of β‐tubulin. The two compounds bind in a very similar hairpin conformation, as previously observed in solution. However, they stabilize the M‐loop of β‐tubulin differently: KS‐1‐199‐32 induces an M‐loop helical conformation that is not observed for DDM. In the context of the microtubule structure, both MSAs connect the β‐tubulin helices H6 and H7 and loop S9–S10 with the M‐loop. This is similar to the structural effects elicited by epothilone A, but distinct from paclitaxel. Together, our data reveal differential binding mechanisms of DDM and KS‐1‐199‐32 on tubulin. Microtubule‐stabilizing agents: Discodermolide (DMM) and KS‐1‐199‐32 are microtubule‐stabilizing agents with potent anticancer activity. X‐ray crystallography shows that both compounds bind to the taxane site on β‐tubulin with distinct features. The data define the mechanisms of binding of DDM and KS‐1‐199‐32 on tubulin and microtubules.