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An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach
[Image: see text] Protein–protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein–protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here,...
| Autores principales: | , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical
Society
2021
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237268/ https://www.ncbi.nlm.nih.gov/pubmed/34076416 http://dx.doi.org/10.1021/acs.jmedchem.1c00401 |
| _version_ | 1783714695890337792 |
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| author | Wolter, Madita Valenti, Dario Cossar, Peter J. Hristeva, Stanimira Levy, Laura M. Genski, Thorsten Hoffmann, Torsten Brunsveld, Luc Tzalis, Dimitrios Ottmann, Christian |
| author_facet | Wolter, Madita Valenti, Dario Cossar, Peter J. Hristeva, Stanimira Levy, Laura M. Genski, Thorsten Hoffmann, Torsten Brunsveld, Luc Tzalis, Dimitrios Ottmann, Christian |
| author_sort | Wolter, Madita |
| collection | PubMed |
| description | [Image: see text] Protein–protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein–protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex. |
| format | Online Article Text |
| id | pubmed-8237268 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2021 |
| publisher | American Chemical
Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-82372682021-07-06 An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach Wolter, Madita Valenti, Dario Cossar, Peter J. Hristeva, Stanimira Levy, Laura M. Genski, Thorsten Hoffmann, Torsten Brunsveld, Luc Tzalis, Dimitrios Ottmann, Christian J Med Chem [Image: see text] Protein–protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein–protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex. American Chemical Society 2021-06-02 2021-06-24 /pmc/articles/PMC8237268/ /pubmed/34076416 http://dx.doi.org/10.1021/acs.jmedchem.1c00401 Text en © 2021 The Authors. Published by American Chemical Society 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 Valenti, Dario Cossar, Peter J. Hristeva, Stanimira Levy, Laura M. Genski, Thorsten Hoffmann, Torsten Brunsveld, Luc Tzalis, Dimitrios Ottmann, Christian An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach |
| title | An Exploration
of Chemical Properties Required for
Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing
a Reversible Covalent Tethering Approach |
| title_full | An Exploration
of Chemical Properties Required for
Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing
a Reversible Covalent Tethering Approach |
| title_fullStr | An Exploration
of Chemical Properties Required for
Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing
a Reversible Covalent Tethering Approach |
| title_full_unstemmed | An Exploration
of Chemical Properties Required for
Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing
a Reversible Covalent Tethering Approach |
| title_short | An Exploration
of Chemical Properties Required for
Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing
a Reversible Covalent Tethering Approach |
| title_sort | exploration
of chemical properties required for
cooperative stabilization of the 14-3-3 interaction with nf-κb—utilizing
a reversible covalent tethering approach |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237268/ https://www.ncbi.nlm.nih.gov/pubmed/34076416 http://dx.doi.org/10.1021/acs.jmedchem.1c00401 |
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