Abstract

In recent years, YEATS domains have emerged as readers of histone post-translational modifications (HPTM) alongside bromodomains, PHD fingers and others. Like bromodomains, they recognise acylation on the ε-carbon atom of lysine and are implicated as actors in a range of cancer types. They appear to favour crotonylation over acetylation and even though they are both associated with active transcription, the significance of crotonylation is poorly understood.

Structurally, YEATS domains form an immunoglobulin like fold that recognises the acyl group of the modified lysines in an aromatic cage at the tip of the β-sheets while the rest of the peptide is in contact with the mostly flat surface of the fold. The aromatic cage is open to both sides and thus allows recognition of larger lysine modifications compared to other acyl-readers (e.g. Bromodomains, which generally only recognise acetylation).

Functionally, YEATS domain containing proteins act as reader and scaffold proteins that direct protein complexes involved in transcription to acylated histones.

Here, we are showing the current progress in developing selective inhibitors for members of the YEATS family with the ultimate goal of developing chemical probes for each member of the family.