Differential Modulation of Nuclear Receptor LRH‑1 through Targeting Buried and Surface Regions of the Binding Pocket

Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding and residues at the mouth of the pocket to mimic interactions made by phospholipids. Here, we unite these two designs into one molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep versus surface polar regions in the pocket. While deep pocket contacts convey high affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.

肝脏受体同源物-1（Liver receptor homologue-1, LRH-1）是一种磷脂感应型核受体，已展现出作为缓解肠道炎症与肝脏代谢紊乱药物靶点的潜力。该受体拥有一个较大的配体结合口袋，但开发其合成调节剂始终颇具挑战。本团队近期通过两种截然不同的策略，成功获得了强效且高效的LRH-1激动剂：我们靶向口袋深处的氨基酸残基以增强化合物结合能力，同时靶向口袋入口处的残基以模拟磷脂所介导的相互作用。本研究将这两种设计思路整合至单个分子中，合成了迄今为止活性最强的LRH-1激动剂。通过整合全转录组学、生物化学与结构生物学研究手段，我们证实，选择性调控可通过靶向口袋内的深层极性区域与表面极性区域来实现。尽管与口袋深层的相互作用可带来高亲和力，但与口袋入口的相互作用则主导变构调控，并能在培养细胞中诱导出类似磷脂介导的转录应答。