7b9c | pdb_00007b9c
Structure of a minimal SF3B core in complex with spliceostatin A (form I)
Structural highlights
FunctionPHF5A_HUMAN Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha. Also involved in pre-mRNA splicing.[1] Publication Abstract from PubMedIntron 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. Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors.,Cretu C, Gee P, Liu X, Agrawal A, Nguyen TV, Ghosh AK, Cook A, Jurica M, Larsen NA, Pena V Nat Commun. 2021 Jul 23;12(1):4491. doi: 10.1038/s41467-021-24741-1. PMID:34301950[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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