Division of Biological Chemistry and Drug Discovery, James Black Centre, School of Life Sciences , University of Dundee , Dow Street , Dundee , DD1 5EH , United Kingdom.
Department of Chemistry , University of Cambridge , Cambridge CB2 1EW , United Kingdom.
J Med Chem. 2018 Aug 23;61(16):7387-7393. doi: 10.1021/acs.jmedchem.8b00842. Epub 2018 Aug 8.
Beyond the targeting of E3 ubiquitin ligases to inhibit protein homeostasis, E3 ligase binders can be repurposed as targeted protein degraders (PROTACs or molecular glues). We sought to identify new binders of the VHL E3 ligase by biophysical fragment-based screening followed by X-ray crystallographic soaking. We identified fragments binding at the ElonginC:Cullin2 interface and a new cryptic pocket in VHL, along with other potential ligandable sites predicted computationally and found to bind solvent molecules in crystal structures. The elucidated interactions provide starting points for future ligand development.
除了针对 E3 泛素连接酶来抑制蛋白质动态平衡外，E3 连接酶配体还可以被重新用作靶向蛋白降解剂（PROTAC 或分子胶）。我们通过基于生物物理的片段筛选，然后进行 X 射线晶体学浸泡，来寻找 VHL E3 连接酶的新配体。我们鉴定出与 ElonginC:Cullin2 界面和 VHL 中新的隐蔽口袋结合的片段，以及其他通过计算预测的潜在配体结合位点，并在晶体结构中发现结合溶剂分子。阐明的相互作用为未来的配体开发提供了起点。
