Targeting ligandable pockets on PHD zinc finger domains by a fragment-based approach

Anastasia Amato, Xavier Lucas, Alessio Bortoluzzi, David Wright, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
149 Downloads (Pure)

Abstract

Plant homeodomain (PHD) zinc fingers are histone reader domains that often associate 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 targets.
Original languageEnglish
Pages (from-to)915-921
Number of pages7
JournalACS Chemical Biology
Volume13
Issue number4
Early online date12 Mar 2018
DOIs
Publication statusPublished - 20 Apr 2018

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