Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs

Bioorg Chem. 2011 Feb;39(1):42-7. doi: 10.1016/j.bioorg.2010.10.004. Epub 2010 Oct 28.

Abstract

Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a negatively charged surface on the enzyme to interact with the histone tail.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Coenzyme A / chemistry
  • Coenzyme A / pharmacology
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / pharmacology
  • p300-CBP Transcription Factors / antagonists & inhibitors*
  • p300-CBP Transcription Factors / chemistry
  • p300-CBP Transcription Factors / metabolism*

Substances

  • Enzyme Inhibitors
  • Peptides
  • p300-CBP Transcription Factors
  • Coenzyme A