How to glue – structure elucidation of weak protein complexes for the rational design of molecular glues

Molecular glues are a type of proximity-inducing compound and are particularly popular as chemical degraders.

The discovery of nearly all molecular glues have been serendipitous, where the first compounds to be determined as molecular glues were part of treatments well before their mode of action was known.

In the 1990s it became clear that these binders induce proximity between protein domains, thereby stabilizing otherwise non-productive complexes. Despite their potential, the rational design strategies for molecular glues are still lacking.

In large, this is a result of the challenges in obtaining structural information on the complex one wishes to target in absence of the molecular glue.

Complex formation in absence of any small molecule binder is weak to non-observable, complicating structure elucidation of the free complex.The aim of this project is to design a strategy that allows for structural investigation of these weak protein complexes using a combination of NMR and cryoEM methods.

An integrative structural biology approach will be developed, using the DCAF11 and DCAF16 interactions with BRD2 and BRD4 as a model to study weak protein-protein interactions. The obtained structural information on the DCAF:BRD complexes will aid in future rational design of molecular glues. Furthermore, the developed strategy can be used in future studies of weak protein-protein interactions in general.