9F4L

UP1 in complex with Z104584152

Summary for 9F4L

• Entry DOI: 10.2210/pdb9f4l/pdb
• Descriptor: Heterogeneous nuclear ribonucleoprotein A1, N-terminally processed, N,N-dimethyl-N~2~-phenylglycinamide (3 entities in total)
• Functional Keywords: fragment screening, hnrnp a1, up1, rna/dna binding protein, up1-fragment complex, rna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 22535.34

Authors

Dunnett, L.,Prischi, F. (deposition date: 2024-04-28, release date: 2024-05-08, Last modification date: 2025-01-22)

Primary citation

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.
Biorxiv, 2024

PubMed Abstract: The human heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is a prototypical RNA-binding protein essential in 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 modulates its RNA binding activities. Here, using a combination of Molecular Dynamics (MD) simulations and graph neural network pockets 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 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 which extensively samples UP1 functional regions involved in RNA recognition and binding, as well as mapping 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, provides 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: 39763864
DOI: 10.1101/2024.12.17.628909

Experimental method

X-RAY DIFFRACTION (1.4 Å)