Structural Basis of Microtubule Stabilization by Discodermolide

Andrea E. Prota; Katja Bargsten; Mariano Redondo-Horcajo; Amos B. Smith; Chia Ping H. Yang; Hayley M. McDaid; Ian Paterson; Susan B. Horwitz; José Fernando Díaz; Michel O. Steinmetz

doi:10.1002/cbic.201600696

Structural Basis of Microtubule Stabilization by Discodermolide

Andrea E. Prota, Katja Bargsten, Mariano Redondo-Horcajo, Amos B. Smith, Chia Ping H. Yang, Hayley M. McDaid, Ian Paterson, Susan B. Horwitz, José Fernando Díaz, Michel O. Steinmetz

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English (US)
Pages (from-to)	905-909
Number of pages	5
Journal	ChemBioChem
Volume	18
Issue number	10
DOIs	https://doi.org/10.1002/cbic.201600696
State	Published - May 18 2017

Keywords

X-ray crystallography
drug design
microtubules
molecular mechanism of action
structure elucidation

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Organic Chemistry

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10.1002/cbic.201600696

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title = "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 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.",

keywords = "X-ray crystallography, drug design, microtubules, molecular mechanism of action, structure elucidation",

author = "Prota, {Andrea E.} and Katja Bargsten and Mariano Redondo-Horcajo and Smith, {Amos B.} and Yang, {Chia Ping H.} and McDaid, {Hayley M.} and Ian Paterson and Horwitz, {Susan B.} and {Fernando D{\'i}az}, Jos{\'e} and Steinmetz, {Michel O.}",

note = "Publisher Copyright: {\textcopyright} 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

year = "2017",

month = may,

day = "18",

doi = "10.1002/cbic.201600696",

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AU - Prota, Andrea E.

AU - Bargsten, Katja

AU - Redondo-Horcajo, Mariano

AU - Smith, Amos B.

AU - Yang, Chia Ping H.

AU - McDaid, Hayley M.

AU - Paterson, Ian

AU - Horwitz, Susan B.

AU - Fernando Díaz, José

AU - Steinmetz, Michel O.

PY - 2017/5/18

Y1 - 2017/5/18

N2 - 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.

AB - 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.

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Structural Basis of Microtubule Stabilization by Discodermolide

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