@article{04307c30abad42a294b88b46e94633be,
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 = "Funding Information: We thank Vincent Olieric and Meitian Wang for excellent technical assistance with the collection of X-ray data at beamline X06DA of the Swiss Light Source (Paul Scherrer Institut, Villigen PSI, Switzerland). We also thank Dr. Onur Atasoylu for valuable discussion. This work was supported by grants from the Ministerio de Economia y Competitividad (BFU2016-75319-R (AEI/FEDER, UE), to J.F.D), the NIH (National Cancer Institute) grant CA077263 (A.B.S., H.M.D. and S.B.H.), the National Foundation for Cancer Research (A.B.S. and S.B.H.), the Breast Cancer Research Foundation (H.M.D. and S.B.H.) and the Swiss National Science Foundation (31003A_166608; to M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature—from natural products chemistry to drug discovery” and the COST action CM1470. Coordinates have been deposited at the Protein Data Bank under accession numbers 5LXT (T2R-TTL–DDM) and 5LXS (T2R-TTL–KS-1-199-32). Tubulin residue numbering is as defined in L{\"o}we et al. Publisher Copyright: {\textcopyright} 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",
year = "2017",
month = may,
day = "18",
doi = "10.1002/cbic.201600696",
language = "English (US)",
volume = "18",
pages = "905--909",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley-VCH Verlag",
number = "10",
}