Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds

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

doi:10.1016/j.molcel.2018.03.011

Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds

Mol Cell. 2018 Apr 19;70(2):265-273.e8. doi: 10.1016/j.molcel.2018.03.011. Epub 2018 Apr 12.

Authors

Affiliations

¹ Research Group Macromolecular Crystallography, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
² H3 Biomedicine, Inc., Cambridge, MA 03129, USA.
³ Department of Cellular Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
⁴ Research Group Macromolecular Crystallography, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. Electronic address: [email protected].

PMID: 29656923
DOI: 10.1016/j.molcel.2018.03.011

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.

Keywords: A complex; SF3b; alternative splicing; antitumor drug; branch site; pre-mRNA splicing; spliceosome; splicing modulator.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / metabolism
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Binding Sites
Carrier Proteins / metabolism
Cell Proliferation / drug effects
Drug Design
Epoxy Compounds / chemistry
Epoxy Compounds / metabolism
Epoxy Compounds / pharmacology*
HCT116 Cells
HeLa Cells
Humans
Macrolides / chemistry
Macrolides / metabolism
Macrolides / pharmacology*
Models, Molecular
Multiprotein Complexes
Phosphoproteins / chemistry
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Protein Binding
Protein Conformation
RNA Precursors / genetics
RNA Precursors / metabolism
RNA Splicing / drug effects*
RNA Splicing Factors / chemistry
RNA Splicing Factors / genetics
RNA Splicing Factors / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA-Binding Proteins
Sf9 Cells
Structure-Activity Relationship
Trans-Activators

Substances

Antineoplastic Agents
Carrier Proteins
Epoxy Compounds
Macrolides
Multiprotein Complexes
PHF5A protein, human
Phosphoproteins
RNA Precursors
RNA Splicing Factors
RNA, Messenger
RNA-Binding Proteins
SF3B1 protein, human
Trans-Activators
pladienolide B
Adenosine