Abstract
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.
Original language | English |
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Pages (from-to) | 21-28 |
Number of pages | 8 |
Journal | Current Research in Structural Biology |
Volume | 4 |
Early online date | 29 Dec 2021 |
DOIs | |
Publication status | Published - 2022 |
Keywords
- 14-3-3 /protein-protein interactions stabilizers
- Amot-p130
- Fragment-based drug discovery
- Ligandability
- X-ray crystallography
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology