Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds.

Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds.

Molecular cell (2018-04-17)

Constantin Cretu, Anant A Agrawal, Andrew Cook, Cindy L Will, Peter Fekkes, Peter G Smith, Reinhard Lührmann, Nicholas Larsen, Silvia Buonamici, Vladimir Pena

PMID29656923

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.

MATERIALS

Product Number

Brand

Product Description

F3165

Sigma-Aldrich

Monoclonal ANTI-FLAG^® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)

71397

Sigma-Aldrich

Rosetta 2(DE3) Competent Cells - Novagen, Novagen′s Rosetta 2 host strains are BL21 derivatives designed to enhance the expression of eukaryotic proteins that contain codons rarely used in E. coli.