Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 interaction with Semi-Synthetic Natural Products

Madita Wolter, Pim de Vink, Joao Filipe Neves, Sonja Srdanovic, Yusuke Higuchi, Nobuo Kato, Andrew J Wilson, Isabelle Landrieu, Luc Brunsveld, Christian Ottmann (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)

Abstract

Natural compounds are an important class of potent drug molecules including some retrospectively found to act as stabilizers of protein-protein interactions (PPIs). However, the design of synthetic PPI stabilizers remains an understudied approach. To date, there are limited examples where cooperativity has been utilized to guide the optimization of a PPI stabilizer. The 14-3-3 scaffold proteins provide an excellent platform to explore PPI stabilization because these proteins mediate several hundred PPIs, and a class of natural compounds - the fusicoccanes - are known to stabilize a subset of 14-3-3 protein interactions. 14-3-3 has been reported to negatively regulate the p65 subunit of the NF-κB transcription factor, qualifying this protein complex as a potential target for drug discovery in order to control cell proliferation. Here, we report the high-resolution crystal structures of two 14-3-3 binding motifs of p65 in complex with 14-3-3. A semi-synthetic natural product derivative - DP-005 - binds to an interface pocket of the p65/14-3-3 complex and concomitantly stabilizes it. Cooperativity analyses of this interaction, and other disease relevant 14-3-3-PPIs, demonstrated selectivity of DP-005 for the p65/14-3-3 complex. The adaptation of a cooperative binding model provided a general approach to characterize stabilization and to assay for selectivity of PPI stabilizers.

Original languageEnglish
Pages (from-to)11772–11783
Number of pages12
JournalJournal of the American Chemical Society
Volume142
Issue number27
DOIs
Publication statusPublished - 8 Jul 2020

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