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Oral Sessions
Day 4, June 25（Wed.） 12:10-12:25
Room C (Top of Yaima)
- 4C-O1-1210
Chemical Proteomics and Cross-linking Mass Spectrometry for Identification of Protein-protein Interactions of drug-protein interactome
(IMCB, A*STAR)
oZheng Ser, Alicia Ong, Radoslaw Sobota
Elucidation of drug mechanism of action enables understanding of on-target and off-target binding of drugs, which in turn facilities development of more efficacious drugs. A common approach to identifying drug-protein interactions is chemical proteomics, where small molecule drugs are modified with affinity handles or other functional groups and the resultant protein binders are identified and quantified by mass spectrometry proteomics. Here, we developed a method that incorporates protein-protein cross-linking with chemical proteomics for identification of both direct and indirect protein binders of the small molecule JQ-1. Incorporation of cross-linking retains enrichment of BRD4, the protein target of JQ-1. Cross-linking chemical proteomics identifies a larger number of BRD4 interacting proteins, with related functions to chromosome organization and transcription, consistent with BRD4 functions. We further apply cross-linking mass spectrometry to the cross-linking chemical proteomics samples to identify protein-protein cross-links which further inform about the protein-protein interactions. Apart from the small molecule JQ-1, we also tested our method on a single-stranded DNA aptamer that targets an RNA-binding protein. Taken together, our chemical proteomics and cross-linking mass spectrometry approach enables elucidation of drug-protein interactions for both small molecule and nucleic acid molecules.