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

DOI: 10.1016/j.crstbi.2021.12.003 DOI Help

Authors: Federica Centorrino (Eindhoven University of Technology) , Blaž Andlovic (Eindhoven University of Technology) , Peter Cossar (Eindhoven University of Technology) , Luc Brunsveld (Eindhoven University of Technology) , Christian Ottmann (Eindhoven University of Technology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Current Research In Structural Biology , VOL 4 , PAGES 21 - 28

State: Published (Approved)
Published: January 2022

Open Access Open Access

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.

Journal Keywords: Amot-p13014-3-3 /protein-protein interactions stabilizers; Fragment-based drug discovery; X-ray crystallography; Ligandability

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: PII at Deutsches Elektronen-Synchrotron (DESY) PETRA-III

Added On: 04/01/2022 11:52


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)