Journal
NATURE CHEMICAL BIOLOGY
Volume 13, Issue 1, Pages 21-29Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2217
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Funding
- FRISBI [ANR-10-INSB-05-02]
- EMBL Interdisciplinary Postdoc Programme under Marie Sklodowska-Curie actions [291772]
- ANR [15-CE12-0005-02]
- Worldwide Cancer Research foundation [16-0280]
- INCa
- Fondation pour la Recherche Medicale
- Fondation ARC
- NIH [GM105933, DK107868, GM115961]
- GOAL [ANR-10-LABX-49-01]
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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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