Structural basis of splicing modulation by antitumor macrolide compounds.

Cretu, C.; Agrawal, A. A.; Cook, A.; Will, C. L.; Fekkes, P.; Smith, P. G.,; Lührmann, R.; Larsen, N.; Buonamici, S.; Pena, V.

doi:10.1016/j.molcel.2018.03.011

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

Structural basis of splicing modulation by antitumor macrolide compounds.

MPS-Authors

/persons/resource/persons199462

Cretu, C.
Research Group of Macromolecular Crystallography, MPI for Biophysical Chemistry, Max Planck Society;

/persons/resource/persons16028

Will, C. L.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons15470

Lührmann, R.
Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons15625

Pena, V.
Research Group of Macromolecular Crystallography, MPI for Biophysical Chemistry, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

2578317_Suppl_1.pdf
(Supplementary material), 2MB

2578317_Suppl_2.pdf
(Supplementary material), 5MB

Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0001-2921-C

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.