Sep 2026· Proceedings of the National Academy of Sciences of the United States of America· Vol 123· 0 citations· 32 references
Medicine
TL;DR
The crystal structures of recurrent hotspot mutations in the CREBBP acetyltransferase are solved and it is shown that the arginine 1446 hotspot has a unique impact on substrate binding and acetyltransferase activity.
Abstract
Significance Epigenetic deregulation is an emerging and therapeutically targetable hallmark of cancer but the structural and functional impact of mutations in epigenetic regulators remain largely uncharacterized. Here we solve the crystal structures of recurrent hotspot mutations in the CREBBP acetyltransferase and show through biochemical and molecular assays that the arginine 1446 hotspot has a unique impact on substrate binding and acetyltransferase activity. This provides a framework with which mutations of CREBBP can be interpreted based upon their predicted impact on substrate binding or catalysis, linked with differences in EP300 dependence for maintenance of regulatory element activity.
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