Plant homeodomain (PHD) zinc fingers are histone reader domains that are often
associated with human diseases. Despite this, they constitute a poorly targeted
class of readers, suggesting low ligandability. Here, we describe a successful
fragment-based campaign targeting PHD fingers from the proteins BAZ2A and BAZ2B
as model systems. We validated a pool of in silico fragments both biophysically
and structurally and solved the first crystal structures of PHD zinc fingers in
complex with fragments bound to an anchoring pocket at the histone binding site.
The best-validated hits were found to displace a histone H3 tail peptide in
competition assays. This work identifies new chemical scaffolds that provide
suitable starting points for future ligand optimization using structure-guided
approaches. The demonstrated ligandability of the PHD reader domains could pave
the way for the development of chemical probes to drug this family of epigenetic
readers.
Links
