SWI/SNF subunit BAF155 N-terminus structure informs the impact of cancer-associated mutations and reveals a potential drug binding site

Allen et al. determine crystal structure of the N-terminus of SWI/SNF chromatin remodelling factor subunit BAF155. They identify an interconnected structure of MarR-like, BRCT and chromodomains, visualise the potential effect of cancer-associated missense mutations and suggest a binding site and target for small molecule inhibitors. SWI/SNF (BAF) chromatin remodelling complexes are key regulators of gene expression programs, and attractive drug targets for cancer therapies. Here we show that the N-terminus of the BAF155/SMARCC1 subunit contains a putative DNA-binding MarR-like domain, a chromodomain and a BRCT domain that are interconnected to each other to form a distinct module. In this structure the chromodomain makes interdomain interactions and has lost its canonical function to bind to methylated lysines. The structure provides new insights into the missense mutations that target this module in cancer. This study also reveals two adjacent, highly-conserved pockets in a cleft between the domains that form a potential binding site, which can be targeted with small molecules, offering a new strategy to target SWI/SNF complexes.

Automated summary

The crystal structure of the N-terminus of SWI/SNF chromatin remodelling factor subunit BAF155 was determined, revealing an interconnected structure of MarR-like, BRCT, and chromodomains. The study shows potential effects of cancer-associated missense mutations and suggests a binding site and target for small molecule inhibitors, offering a new strategy to target SWI/SNF complexes.