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Structural Basis of Microtubule Stabilization by Discodermolide.

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 ?-tubulin. The two compounds bind in a very similar hairpin conformation, as previously observed in solution. However, they stabilize the M-loop of ?-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 ?-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.

SUBMITTER: Prota AE

PROVIDER: S-EPMC5559732 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Structural Basis of Microtubule Stabilization by Discodermolide.

Prota Andrea E AE Bargsten Katja K Redondo-Horcajo Mariano M Smith Amos B AB Yang Chia-Ping H CH McDaid Hayley M HM Paterson Ian I Horwitz Susan B SB Fernando Díaz José J Steinmetz Michel O MO

Chembiochem : a European journal of chemical biology 20170327 10

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 D ...[more]

PMID: 28207984

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