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

DOI: 10.1038/s42003-021-02050-z DOI Help

Authors: Mark D. Allen (UKRI MRC Laboratory of Molecular Biology) , Stefan M. V. Freund (UKRI MRC Laboratory of Molecular Biology) , Mark Bycroft (UKRI MRC Laboratory of Molecular Biology) , Giovanna Zinzalla (Karolinska Institutet)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 4

State: Published (Approved)
Published: May 2021

Open Access Open Access

Abstract: 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.

Journal Keywords: Cancer therapy; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 11/05/2021 09:10

Documents:
s42003-021-02050-z.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)