Chemical basis for arginine citrullination by human PAD4.

Peptidyl arginine deiminase 4 (PAD4)-catalysed citrullination of arginine residues in histone proteins plays an important role in eukaryotic gene regulation. Enzyme assays with histone H4 peptides possessing the simplest arginine mimics demonstrate that human PAD4 exhibits narrow substrate selectivity. Computational analyses reveal that the arginine substrate recognition is governed by strong noncovalent interactions with PAD4 and energetically favourable desolvation of the PAD4 active site.