Division of Biological Chemistry and Drug Discovery, School of Life Sciences , University of Dundee , James Black Centre, Dow Street , Dundee DD1 5EH , United Kingdom.
ACS Chem Biol. 2018 Apr 20;13(4):915-921. doi: 10.1021/acschembio.7b01093. Epub 2018 Mar 20.
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.
植物同源结构域（PHD）锌指是与人类疾病相关的组蛋白读码域，但它们属于靶向性较差的读码域，提示其配体结合能力较低。在此，我们以 BAZ2A 和 BAZ2B 这两种蛋白的 PHD 手指为模型系统，描述了一个成功的基于片段的靶向研究。我们通过生物物理和结构方法对虚拟片段库进行了验证，并首次解析了与组蛋白结合位点上的锚定位点结合的片段结合的 PHD 锌指的晶体结构。在竞争测定中，最佳验证的命中物被发现可置换组蛋白 H3 尾部肽。这项工作确定了新的化学支架，为使用基于结构的方法进行未来配体优化提供了合适的起点。所证明的 PHD 读码域的配体结合能力为开发针对该组表观遗传读码器的化学探针铺平了道路。
