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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Current Research in Structural Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2665928X21000337 |
| _version_ | 1811292312750260224 |
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| author | Federica Centorrino Blaž Andlovic Peter Cossar Luc Brunsveld Christian Ottmann |
| author_facet | Federica Centorrino Blaž Andlovic Peter Cossar Luc Brunsveld Christian Ottmann |
| author_sort | Federica Centorrino |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T04:43:33Z |
| format | Article |
| id | doaj.art-9aa805d739e247f28175f48fe4521eb3 |
| institution | Directory Open Access Journal |
| issn | 2665-928X |
| language | English |
| last_indexed | 2024-04-13T04:43:33Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Structural Biology |
| spelling | doaj.art-9aa805d739e247f28175f48fe4521eb32022-12-22T03:01:55ZengElsevierCurrent Research in Structural Biology2665-928X2022-01-0142128Fragment-based exploration of the 14-3-3/Amot-p130 interfaceFederica Centorrino0Blaž Andlovic1Peter Cossar2Luc Brunsveld3Christian Ottmann4Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P. O. Box 513, 5600 MB, Eindhoven, the NetherlandsLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P. O. Box 513, 5600 MB, Eindhoven, the NetherlandsLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P. O. Box 513, 5600 MB, Eindhoven, the NetherlandsLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P. O. Box 513, 5600 MB, Eindhoven, the NetherlandsCorresponding author.; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P. O. Box 513, 5600 MB, Eindhoven, the NetherlandsThe 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.http://www.sciencedirect.com/science/article/pii/S2665928X21000337Amot-p13014-3-3 /protein-protein interactions stabilizersFragment-based drug discoveryX-ray crystallographyLigandability |
| spellingShingle | Federica Centorrino Blaž Andlovic Peter Cossar Luc Brunsveld Christian Ottmann Fragment-based exploration of the 14-3-3/Amot-p130 interface Current Research in Structural Biology Amot-p130 14-3-3 /protein-protein interactions stabilizers Fragment-based drug discovery X-ray crystallography Ligandability |
| 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 | Amot-p130 14-3-3 /protein-protein interactions stabilizers Fragment-based drug discovery X-ray crystallography Ligandability |
| url | http://www.sciencedirect.com/science/article/pii/S2665928X21000337 |
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