Targeting the conserved active site of splicing machines with specific and selective small molecule modulators.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 Jun 2024
19 Jun 2024
Historique:
received:
21
06
2023
accepted:
06
05
2024
medline:
20
6
2024
pubmed:
20
6
2024
entrez:
19
6
2024
Statut:
epublish
Résumé
The self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome and retro-transposable elements of pharmacological and biotechnological importance. Integrating enzymatic, crystallographic, and simulation studies, we demonstrate how these introns recognize small molecules through their conserved active site. These RNA-binding small molecules selectively inhibit the two steps of splicing by adopting distinctive poses at different stages of catalysis, and by preventing crucial active site conformational changes that are essential for splicing progression. Our data exemplify the enormous power of RNA binders to mechanistically probe vital cellular pathways. Most importantly, by proving that the evolutionarily-conserved RNA core of splicing machines can recognize small molecules specifically, our work provides a solid basis for the rational design of splicing modulators not only against bacterial and organellar introns, but also against the human spliceosome, which is a validated drug target for the treatment of congenital diseases and cancers.
Identifiants
pubmed: 38898052
doi: 10.1038/s41467-024-48697-0
pii: 10.1038/s41467-024-48697-0
doi:
Substances chimiques
Small Molecule Libraries
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4980Subventions
Organisme : Fondation ARC pour la Recherche sur le Cancer (ARC Foundation for Cancer Research)
ID : PJA-20191209284
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-10-INSB-05-02
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-17-EURE-0003
Informations de copyright
© 2024. The Author(s).
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