7B91

Structure of a minimal SF3B core in complex with pladienolide D (form I)

Summary for 7B91

• Entry DOI: 10.2210/pdb7b91/pdb
• Related: 5IFE 6EN4 7B0I
• Descriptor: Splicing factor 3B subunit 3, Splicing factor 3B subunit 5, Splicing factor 3B subunit 1, ... (7 entities in total)
• Functional Keywords: sf3b, pre-mrna splicing, splicing modulator, pladienolide d, splicing
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 219906.66

Authors

Cretu, C.,Pena, V. (deposition date: 2020-12-13, release date: 2021-08-04, Last modification date: 2024-01-31)

Primary citation

Cretu, C.,Gee, P.,Liu, X.,Agrawal, A.,Nguyen, T.V.,Ghosh, A.K.,Cook, A.,Jurica, M.,Larsen, N.A.,Pena, V.
Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors.
Nat Commun, 12:4491-4491, 2021

PubMed Abstract: 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.

PubMed: 34301950
DOI: 10.1038/s41467-021-24741-1

Experimental method

X-RAY DIFFRACTION (3 Å)