Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers
Eline Sijbesma, Kenneth K. Hallenbeck, Sebastian A. Andrei, Reanne R. Rust, Joris M. C. Adriaans, Luc Brunsveld, Michelle R. Arkin, Christian Ottmann
Abstract
The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.