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  Structural basis of splicing modulation by antitumor macrolide compounds.

Cretu, C., Agrawal, A. A., Cook, A., Will, C. L., Fekkes, P., Smith, P. G., et al. (2018). Structural basis of splicing modulation by antitumor macrolide compounds. Molecular Cell, 70(2), 265-273. doi:10.1016/j.molcel.2018.03.011.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-2921-C Version Permalink: http://hdl.handle.net/21.11116/0000-0003-479C-E
Genre: Journal Article

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2578317.pdf (Publisher version), 4MB
 
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 Creators:
Cretu, C.1, Author              
Agrawal, A. A., Author
Cook, A., Author
Will, C. L.2, Author              
Fekkes, P., Author
Smith, P. G.,, Author
Lührmann, R.2, Author              
Larsen, N., Author
Buonamici, S., Author
Pena, V.1, Author              
Affiliations:
1Research Group of Macromolecular Crystallography, MPI for Biophysical Chemistry, Max Planck Society, ou_2035293              
2Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              

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Free keywords: A complex; SF3b; alternative splicing; antitumor drug; branch site; pre-mRNA splicing; spliceosome; splicing modulator
 Abstract: SF3B is a multi-protein complex essential for branch site (BS) recognition and selection during pre-mRNA splicing. Several splicing modulators with antitumor activity bind SF3B and thereby modulate splicing. Here we report the crystal structure of a human SF3B core in complex with pladienolide B (PB), a macrocyclic splicing modulator and potent inhibitor of tumor cell proliferation. PB stalls SF3B in an open conformation by acting like a wedge within a hinge, modulating SF3B's transition to the closed conformation needed to form the BS adenosine-binding pocket and stably accommodate the BS/U2 duplex. This work explains the structural basis for the splicing modulation activity of PB and related compounds, and reveals key interactions between SF3B and a common pharmacophore, providing a framework for future structure-based drug design.

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Language(s): eng - English
 Dates: 2018-03-242018-04-19
 Publication Status: Published in print
 Pages: -
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.molcel.2018.03.011
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Title: Molecular Cell
Source Genre: Journal
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Pages: - Volume / Issue: 70 (2) Sequence Number: - Start / End Page: 265 - 273 Identifier: -