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

Mark D Allen1, Stefan M V Freund1, Mark Bycroft1,2

  • 1UKRI MRC Laboratory of Molecular Biology, Cambridge, UK.

Communications Biology
|May 6, 2021
PubMed

Insights

The study reveals a new structural module in the BAF155/SMARCC1 protein, crucial for SWI/SNF (BAF) chromatin remodellers. This finding offers a novel strategy for small molecule drug development targeting cancer therapies.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Therapeutics

Background:

  • SWI/SNF (BAF) chromatin remodelling complexes regulate gene expression.
  • These complexes are significant targets for cancer drug development.

Purpose of the Study:

  • To elucidate the structure and function of the N-terminus of the BAF155/SMARCC1 subunit.
  • To identify potential small molecule binding sites for therapeutic targeting.

Main Methods:

  • X-ray crystallography to determine the 3D structure of the BAF155/SMARCC1 N-terminal module.
  • Bioinformatic analysis to identify conserved domains and potential binding pockets.

Main Results:

  • The N-terminus of BAF155/SMARCC1 forms a distinct module comprising MarR-like, chromodomain, and BRCT domains.
  • The chromodomain engages in interdomain interactions, losing its typical methylated lysine binding function.
  • Two adjacent, conserved pockets forming a potential small molecule binding site were identified.

Conclusions:

  • The identified structural module and binding site offer new insights into cancer-associated mutations.
  • This provides a novel strategy for developing small molecule inhibitors targeting SWI/SNF complexes in cancer therapy.

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