In:
ChemBioChem, Wiley, Vol. 18, No. 10 ( 2017-05-18), p. 905-909
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1439-4227
,
1439-7633
DOI:
10.1002/cbic.201600696
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2020469-3
SSG:
12
Permalink