Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors
- Resource Type
- Authors
- Nicholas A. Larsen; Xiang Liu; Patricia Gee; Andrew Cook; Constantin Cretu; Melissa S. Jurica; Vladimir Pena; Anant A. Agrawal; Tuong-Vi Nguyen; Arun K. Ghosh
- Source
- Nature communications, vol 12, iss 1
Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021)
Nature Communications
- Subject
- Models, Molecular
RNA splicing
Protein Conformation
Protein subunit
Science
General Physics and Astronomy
Crystallography, X-Ray
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
Lactones
0302 clinical medicine
Models
Genetics
Humans
snRNP
Spiro Compounds
Strand invasion
030304 developmental biology
X-ray crystallography
Pyrans
Zinc finger
0303 health sciences
Multidisciplinary
U2 Small Nuclear
Crystallography
Chemistry
Cryoelectron Microscopy
Intron
Molecular
General Chemistry
Ribonucleoprotein
DNA
Ribonucleoprotein, U2 Small Nuclear
Introns
Cell biology
Prespliceosome
Pyrones
Spliceosomes
X-Ray
Nucleic Acid Conformation
Generic health relevance
030217 neurology & neurosurgery
Small nuclear ribonucleoprotein
Protein Binding
- Language
Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)—a complex chaperoning the selection of branch and 3′ splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept.
Chemical modulation of intron selection has emerged as a route for cancer therapy. Here, structures of the U2 snRNP’s SF3B module and of prespliceosome- both in complexes with splicing modulators- provide insight into the mechanisms of intron recognition and branch site inactivation.