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Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products

[Image: see text] 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 example...

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Autores principales: Wolter, Madita, de Vink, Pim, Neves, João Filipe, Srdanović, Sonja, Higuchi, Yusuke, Kato, Nobuo, Wilson, Andrew, Landrieu, Isabelle, Brunsveld, Luc, Ottmann, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022324/
https://www.ncbi.nlm.nih.gov/pubmed/32501683
http://dx.doi.org/10.1021/jacs.0c02151
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author Wolter, Madita
de Vink, Pim
Neves, João Filipe
Srdanović, Sonja
Higuchi, Yusuke
Kato, Nobuo
Wilson, Andrew
Landrieu, Isabelle
Brunsveld, Luc
Ottmann, Christian
author_facet Wolter, Madita
de Vink, Pim
Neves, João Filipe
Srdanović, Sonja
Higuchi, Yusuke
Kato, Nobuo
Wilson, Andrew
Landrieu, Isabelle
Brunsveld, Luc
Ottmann, Christian
author_sort Wolter, Madita
collection PubMed
description [Image: see text] 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, which qualifies this protein complex as a potential target for drug discovery 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 semisynthetic 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.
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spelling pubmed-80223242021-04-06 Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products Wolter, Madita de Vink, Pim Neves, João Filipe Srdanović, Sonja Higuchi, Yusuke Kato, Nobuo Wilson, Andrew Landrieu, Isabelle Brunsveld, Luc Ottmann, Christian J Am Chem Soc [Image: see text] 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, which qualifies this protein complex as a potential target for drug discovery 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 semisynthetic 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. American Chemical Society 2020-06-05 2020-07-08 /pmc/articles/PMC8022324/ /pubmed/32501683 http://dx.doi.org/10.1021/jacs.0c02151 Text en Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Wolter, Madita
de Vink, Pim
Neves, João Filipe
Srdanović, Sonja
Higuchi, Yusuke
Kato, Nobuo
Wilson, Andrew
Landrieu, Isabelle
Brunsveld, Luc
Ottmann, Christian
Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products
title Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products
title_full Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products
title_fullStr Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products
title_full_unstemmed Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products
title_short Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products
title_sort selectivity via cooperativity: preferential stabilization of the p65/14-3-3 interaction with semisynthetic natural products
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022324/
https://www.ncbi.nlm.nih.gov/pubmed/32501683
http://dx.doi.org/10.1021/jacs.0c02151
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