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Nat Chem Biol. 2017 Jan;13(1):21-29. doi: 10.1038/nchembio.2217. Epub 2016 Oct 31.

Structure of p300 in complex with acyl-CoA variants.

Author information

European Molecular Biology Laboratory, Grenoble, France.
Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France.
Ben May Department of Cancer Research, The University of Chicago, Chicago, Illinois, USA.


Histone acetylation plays an important role in transcriptional activation. Histones are also modified by chemically diverse acylations that are frequently deposited by p300, a transcriptional coactivator that uses a number of different acyl-CoA cofactors. Here we report that while p300 is a robust acetylase, its activity gets weaker with increasing acyl-CoA chain length. Crystal structures of p300 in complex with propionyl-, crotonyl-, or butyryl-CoA show that the aliphatic portions of these cofactors are bound in the lysine substrate-binding tunnel in a conformation that is incompatible with substrate transfer. Lysine substrate binding is predicted to remodel the acyl-CoA ligands into a conformation compatible with acyl-chain transfer. This remodeling requires that the aliphatic portion of acyl-CoA be accommodated in a hydrophobic pocket in the enzymes active site. The size of the pocket and its aliphatic nature exclude long-chain and charged acyl-CoA variants, presumably explaining the cofactor preference for p300.

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