Fragment-based exploration of the 14-3-3/Amot-p130 interface

Federica Centorrino, Blaž Andlovic, Peter Cossar, Luc Brunsveld, Christian Ottmann

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
14 Downloads (Pure)

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 languageEnglish
Pages (from-to)21-28
Number of pages8
JournalCurrent Research in Structural Biology
Volume4
Early online date29 Dec 2021
DOIs
Publication statusPublished - 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

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