Using native mass spectrometry to determine the strength of molecular glues
Aneika Leney1
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
Approximately 300,000 protein-protein interactions (PPI) occur in human cells. The disruption of these PPIs into their individual protein constituents contributes to many human diseases including cancer and neurodegeneration. Thus, there is a growing interest in the development of drugs that ‘glue’ protein interactions back together. However, the discovery of novel glues has been hindered due to the lack of tools available to monitor PPI stabilisation.
The work presented will focus on the development of native mass spectrometry to aid in the search for novel PPI stabilisers. We focus on the eukaryotic regulatory protein 14-3-3 and its binding partners estrogen receptor ERα, and a peptidyl prolyl isomerase Pin1 and monitor their binding equilibria upon the addition of two different stabilisers, FusA and A28. Both these molecular glues act by different modes of stabilisation that we readily differentiated by tandem mass spectrometry experiments. Overall, the data highlights how native MS is making advances in the discovering of novel molecular glues and the mechanism behind how these glues stabilise protein-protein interactions.
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