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Fragment-based exploration of the 14-3-3/Amot-p130 interface
The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ‘undruggable’ targets and the design of PPIs stabilizers remains a significant challenge. The application of...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743172/ https://www.ncbi.nlm.nih.gov/pubmed/35036934 http://dx.doi.org/10.1016/j.crstbi.2021.12.003 |
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author | Centorrino, Federica Andlovic, Blaž Cossar, Peter Brunsveld, Luc Ottmann, Christian |
author_facet | Centorrino, Federica Andlovic, Blaž Cossar, Peter Brunsveld, Luc Ottmann, Christian |
author_sort | Centorrino, Federica |
collection | PubMed |
description | The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ‘undruggable’ targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the ‘tractability’ of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the ‘ligandability’ of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues. |
format | Online Article Text |
id | pubmed-8743172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-87431722022-01-13 Fragment-based exploration of the 14-3-3/Amot-p130 interface Centorrino, Federica Andlovic, Blaž Cossar, Peter Brunsveld, Luc Ottmann, Christian Curr Res Struct Biol Research Article The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ‘undruggable’ targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the ‘tractability’ of the desired protein target has seen a remarkable development in recent years. In this study, we explore the molecular characteristics of the 14-3-3/Amot-p130 PPI and the conceptual possibility of targeting this interface using X-ray crystallography fragment-based screening. We report the first structural elucidation of the 14-3-3 binding motif of Amot-p130 and the characterization of the binding mode and affinities involved. We made use of fragments to probe the ‘ligandability’ of the 14-3-3/Amot-p130 composite binding pocket. Here we disclose initial hits with promising stabilizing activity and an early-stage selectivity toward the Amot-p130 motifs over other representatives 14-3-3 partners. Our findings highlight the potential of using fragments to characterize and explore proteins' surfaces and might provide a starting point toward the development of small molecules capable of acting as molecular glues. Elsevier 2021-12-29 /pmc/articles/PMC8743172/ /pubmed/35036934 http://dx.doi.org/10.1016/j.crstbi.2021.12.003 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Centorrino, Federica Andlovic, Blaž Cossar, Peter Brunsveld, Luc Ottmann, Christian Fragment-based exploration of the 14-3-3/Amot-p130 interface |
title | Fragment-based exploration of the 14-3-3/Amot-p130 interface |
title_full | Fragment-based exploration of the 14-3-3/Amot-p130 interface |
title_fullStr | Fragment-based exploration of the 14-3-3/Amot-p130 interface |
title_full_unstemmed | Fragment-based exploration of the 14-3-3/Amot-p130 interface |
title_short | Fragment-based exploration of the 14-3-3/Amot-p130 interface |
title_sort | fragment-based exploration of the 14-3-3/amot-p130 interface |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743172/ https://www.ncbi.nlm.nih.gov/pubmed/35036934 http://dx.doi.org/10.1016/j.crstbi.2021.12.003 |
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