8bwf | pdb_00008bwf
PTBP1 RRM1 bound to an allosteric inhibitor
Structural highlights
FunctionPTBP1_HUMAN Plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. Activates exon skipping of its own pre-mRNA during muscle cell differentiation. Binds to the polypyrimidine tract of introns. May promote RNA looping when bound to two separate polypyrimidine tracts in the same pre-mRNA. May promote the binding of U2 snRNP to pre-mRNA. Cooperates with RAVER1 to modulate switching between mutually exclusive exons during maturation of the TPM1 pre-mRNA. Represses the splicing of MAPT/Tau exon 10.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe diverse role of the splicing factor PTBP1 in human cells has been widely studied and was found to be a driver for several diseases. PTBP1 binds RNA through its RNA-recognition motifs which lack obvious pockets for inhibition. A unique transient helix has been described to be part of its first RNA-recognition motif and to be important for RNA binding. In this study, we further confirmed the role of this helix and envisioned its dynamic nature as a unique opportunity to develop stapled peptide inhibitors of PTBP1. The peptides were found to be able to inhibit RNA binding via fluorescence polarization assays and directly occupy the helix binding site as observed by protein crystallography. These cell-permeable inhibitors were validated in cellulo to alter the regulation of alternative splicing events regulated by PTBP1. Our study demonstrates transient secondary structures of a protein can be mimicked by stapled peptides to inhibit allosteric mechanisms. Rationally designed stapled peptides allosterically inhibit PTBP1-RNA-binding.,Schmeing S, Amrahova G, Bigler K, Chang JY, Openy J, Pal S, Posada L, Gasper R, 't Hart P Chem Sci. 2023 Jul 13;14(31):8269-8278. doi: 10.1039/d3sc00985h. eCollection 2023 , Aug 9. PMID:37564416[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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