Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides

Olena S. Tokareva, Kunhua Li, Tara L. Travaline, Ty M. Thomson, Jean-Marie Swiecicki, Mahmoud Moussa, Jessica D. Ramirez, Sean Litchman, Gregory L. Verdine () and John H. McGee ()
Additional contact information
Olena S. Tokareva: FOG Pharmaceuticals Inc.
Kunhua Li: FOG Pharmaceuticals Inc.
Tara L. Travaline: FOG Pharmaceuticals Inc.
Ty M. Thomson: FOG Pharmaceuticals Inc.
Jean-Marie Swiecicki: FOG Pharmaceuticals Inc.
Mahmoud Moussa: FOG Pharmaceuticals Inc.
Jessica D. Ramirez: FOG Pharmaceuticals Inc.
Sean Litchman: FOG Pharmaceuticals Inc.
Gregory L. Verdine: FOG Pharmaceuticals Inc.
John H. McGee: FOG Pharmaceuticals Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Molecules that induce novel interactions between proteins hold great promise for the study of biological systems and the development of therapeutics, but their discovery has been limited by the complexities of rationally designing interactions between three components, and because known binders to each protein are typically required to inform initial designs. Here, we report a general and rapid method for discovering α-helically constrained (Helicon) polypeptides that cooperatively induce the interaction between two target proteins without relying on previously known binders or an intrinsic affinity between the proteins. We show that Helicons are capable of binding every major class of E3 ubiquitin ligases, which are of great biological and therapeutic interest but remain largely intractable to targeting by small molecules. We then describe a phage-based screening method for discovering “trimerizer” Helicons, and apply it to reprogram E3s to cooperatively bind an enzyme (PPIA), a transcription factor (TEAD4), and a transcriptional coactivator (β-catenin).

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42395-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42395-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42395-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().