Reversible covalent imine-tethering for selective stabilization of 14-3-3 hub protein interactions

DOI: 10.1021/jacs.1c03035

Authors: Peter J. Cossar (Eindhoven University of Technology) , Madita Wolter (Eindhoven University of Technology) , Lars Van Dijck (Eindhoven University of Technology) , Dario Valenti (Eindhoven University of Technology; Taros Chemicals GmbH & Co) , Laura M. Levy (Taros Chemicals GmbH & Co) , Christian Ottmann (Eindhoven University of Technology) , Luc Brunsveld (Eindhoven University of Technology)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of The American Chemical Society , VOL 143 , PAGES 8454 - 8464

State: Published (Approved)
Published: June 2021

Abstract: The stabilization of protein complexes has emerged as a promising modality, expanding the number of entry points for novel therapeutic intervention. Targeting proteins that mediate protein–protein interactions (PPIs), such as hub proteins, is equally challenging and rewarding as they offer an intervention platform for a variety of diseases, due to their large interactome. 14-3-3 hub proteins bind phosphorylated motifs of their interaction partners in a conserved binding channel. The 14-3-3 PPI interface is consequently only diversified by its different interaction partners. Therefore, it is essential to consider, additionally to the potency, also the selectivity of stabilizer molecules. Targeting a lysine residue at the interface of the composite 14-3-3 complex, which can be targeted explicitly via aldimine-forming fragments, we studied the de novo design of PPI stabilizers under consideration of potential selectivity. By applying cooperativity analysis of ternary complex formation, we developed a reversible covalent molecular glue for the 14-3-3/Pin1 interaction. This small fragment led to a more than 250-fold stabilization of the 14-3-3/Pin1 interaction by selective interfacing with a unique tryptophan in Pin1. This study illustrates how cooperative complex formation drives selective PPI stabilization. Further, it highlights how specific interactions within a hub proteins interactome can be stabilized over other interactions with a common binding motif.

Journal Keywords: Peptides and proteins; Monomers; Phenyls; Cooperativity; Stabilization

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


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: P11 at Petra III

Added On: 16/06/2021 08:24

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)