8BWF

PTBP1 RRM1 bound to an allosteric inhibitor

8BWF の概要

• エントリーDOI: 10.2210/pdb8bwf/pdb
• 分子名称: Polypyrimidine tract-binding protein 1, Ligand, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: rna binding, protein-peptide interaction, inhibitor, rna binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 32
• 化学式量合計: 181201.37

構造登録者

Schmeing, S.,Vetter, I.,t Hart, P.,Gasper, R. (登録日: 2022-12-06, 公開日: 2023-10-11, 最終更新日: 2023-11-15)

主引用文献

Schmeing, S.,Amrahova, G.,Bigler, K.,Chang, J.Y.,Openy, J.,Pal, S.,Posada, L.,Gasper, R.,'t Hart, P.
Rationally designed stapled peptides allosterically inhibit PTBP1-RNA-binding.
Chem Sci, 14:8269-8278, 2023

PubMed Abstract: The 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 fluorescence polarization assays and directly occupy the helix binding site as observed by protein crystallography. These cell-permeable inhibitors were validated 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.

PubMed: 37564416
DOI: 10.1039/d3sc00985h

実験手法

X-RAY DIFFRACTION (2.9 Å)