emss-75563.pdf (2.11 MB)
Structure of p300 in complex with acyl-CoA variants
journal contributionposted on 2020-03-30, 11:25 authored by Zuzanna Kaczmarska, Esther Ortega, Afsaneh Goudarzi, He Huang, Sunjoo Kim, Jose A Marquez, Yingming Zhao, Saadi Khochbin, Daniel Panne
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.
CitationKaczmarska, Z., Ortega, E., Goudarzi, A. et al. Structure of p300 in complex with acyl-CoA variants. Nat Chem Biol 13, 21–29 (2017). https://doi.org/10.1038/nchembio.2217
- AM (Accepted Manuscript)
Published inNATURE CHEMICAL BIOLOGY
Pagination21 - 29 (9)
PublisherNATURE PUBLISHING GROUP
NotesAtomic coordinates and structure factors of the reported crystal structure have been deposited in the Protein Data Bank under the accession codes: 5LKU (endogenous CoA); 5LKT (butyryl-CoA); 5LKZ (crotonyl-CoA); 5LKX (propionyl-CoA).
Spatial coverageUnited States