9F4Y

UP1 in complex with Z90120418

9F4Y の概要

• エントリーDOI: 10.2210/pdb9f4y/pdb
• 分子名称: Heterogeneous nuclear ribonucleoprotein A1, N-terminally processed, 1-(3,4,5-trimethoxyphenyl)methanamine (3 entities in total)
• 機能のキーワード: fragment screening, hnrnp a1, up1, rna/dna binding protein, up1-fragment complex, rna binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22554.34

構造登録者

Dunnett, L.,Prischi, F. (登録日: 2024-04-28, 公開日: 2024-05-08, 最終更新日: 2025-04-02)

主引用文献

Dunnett, L.,Das, S.,Venditti, V.,Prischi, F.
Enhanced identification of small molecules binding to hnRNPA1 via cryptic pockets mapping coupled with X-ray fragment screening.
J.Biol.Chem., 301:108335-108335, 2025

PubMed Abstract: The human heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is a prototypical RNA-binding protein essential for regulating a wide range of post-transcriptional events in cells. As a multifunctional protein with a key role in RNA metabolism, deregulation of its functions has been linked to neurodegenerative diseases, tumour aggressiveness and chemoresistance, which has fuelled efforts to develop novel therapeutics that modulate its RNA binding activities. Here, using a combination of Molecular Dynamics (MD) simulations and graph neural network pocket predictions, we showed that hnRNPA1 N-terminal RNA binding domain (UP1) contains several cryptic pockets capable of binding small molecules. To identify chemical entities for the development of potent drug candidates and experimentally validate identified druggable hotspots, we carried out a large fragment screening on UP1 protein crystals. Our screen identified 36 hits that extensively sample UP1 functional regions involved in RNA recognition and binding, as well as map hotspots onto novel protein interaction surfaces. We observed a wide range of ligand-induced conformational variation, by stabilisation of dynamic protein regions. Our high-resolution structures, the first of an hnRNP in complex with a fragment or small molecule, provide rapid routes for the rational development of a range of different inhibitors and chemical tools for studying molecular mechanisms of hnRNPA1-mediated splicing regulation.

PubMed: 39984046
DOI: 10.1016/j.jbc.2025.108335

実験手法

X-RAY DIFFRACTION (1.4 Å)