Research Center for Drug Discovery, School of Pharmaceutical Sciences , Sun Yat-Sen University , 132 East Circle at University City , Guangzhou 510006 , China.
J Chem Inf Model. 2019 Jul 22;59(7):3277-3290. doi: 10.1021/acs.jcim.9b00292. Epub 2019 Jun 26.
Liver X receptors (LXRα/β), sensors of cholesterol, are involved in regulation of lipid metabolism and are promising drug targets against many diseases, including atherosclerosis, metabolic syndromes, and cancers. Activation of LXRα can cause adverse effects, and a current focus is a search for LXRβ-selective agonists. An understanding of the ligand-selective mechanisms is critical in the design and identification of LXRβ-selective ligands because the α- and β-isoforms LXRα-Val263 and LXRβ-Ile277 have only minor structural differences in the ligand binding domain (LBD). In this work, and studies were performed. For the first time, we report that the ligand LXRβ-selectivity relies on structural differences between LXRα-Val263 and LXRβ-Ile277 and also on conformational changes at Leu274 and Ala275. These residues are the same in both α- and β-isoforms, but their conformational changes when interacting with selective ligands are different. Mutation studies indicate that replacing both Val263 and Ile277 with alanine residues does not completely nullify the β-selectivity. High β-binding selectivity can be related to the synergistic effects of other residues that interact with the ligand in the LBD, although these residues are identical in both LXRα and LXRβ. This work offers a path to the design and optimization of selective LXRβ agonists.
肝 X 受体 (LXRα/β) 作为胆固醇的感应器，参与脂质代谢的调控，是治疗动脉粥样硬化、代谢综合征和癌症等多种疾病的有希望的药物靶点。LXRα 的激活可能会产生不良反应，目前的研究重点是寻找 LXRβ 选择性激动剂。了解配体选择性机制对于设计和鉴定 LXRβ 选择性配体至关重要，因为 LXRα-Val263 和 LXRβ-Ile277 两种异构体在配体结合域 (LBD) 仅有微小的结构差异。在这项工作中，进行了 和 研究。我们首次报道，配体的 LXRβ 选择性依赖于 LXRα-Val263 和 LXRβ-Ile277 之间的结构差异，以及 Leu274 和 Ala275 处的构象变化。这些残基在两种异构体中是相同的，但它们与选择性配体相互作用时的构象变化不同。突变研究表明，用丙氨酸残基替换 Val263 和 Ile277 并不能完全消除β选择性。高β结合选择性可能与与 LBD 中的配体相互作用的其他残基的协同效应有关，尽管这些残基在 LXRα 和 LXRβ 中是相同的。这项工作为设计和优化选择性 LXRβ 激动剂提供了一条途径。
