Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds
2018 | journal article. A publication with affiliation to the University of Göttingen.
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- Authors
- Cretu, Constantin ; Agrawal, Anant A.; Cook, Andrew; Will, Cindy L.; Fekkes, Peter; Smith, Peter G.; Lührmann, Reinhard ; Larsen, Nicholas; Buonamici, Silvia; Pena, Vladimir
- 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.
- Issue Date
- 2018
- Journal
- Molecular Cell
- Organization
- Max-Planck-Institut für biophysikalische Chemie
- ISSN
- 1097-2765
- eISSN
- 1097-4164
- Language
- English