Structural insight into small molecule action on Frizzleds
Structural insight into small molecule action on Frizzleds
复制标题
DOI：
10.1038/s41467-019-14149-3
复制
发表时间：
2020-01-21
影响因子：
16.6
通讯作者：
Schulte, Gunnar
中科院分区：
文献类型：
--
作者：
Kozielewicz, Pawel;Turku, Ainoleena;Schulte, Gunnar
WNT-Frizzled（FZD）信号在胚胎发育、干细胞调控和组织稳态中起着关键作用。FZD与严重的人类病理学有关，被视为有希望的治疗靶点。尽管付出了巨大的努力，但还没有出现具有明显疗效的小分子药物。在这里，我们将Smoothened激动剂SAG1.3鉴定为FZD（6）的部分激动剂，具有有限的亚型选择性。采用广泛的计算机分析，共振能量转移和基于酶的测定，我们描述了SAG1.3的作用模式。我们确定了SAG1.3与FZD结合的能力（6），并诱导受体的构象变化、G蛋白的募集和激活以及FZD-Dishevelled相互作用的动力学。我们的研究结果提供了FZD可被作用于其七跨膜核心的小分子靶向的原理证明。因此，我们提供了一个起点的结构指导和机制为基础的药物发现过程中，利用FZD作为治疗靶点的潜力。
WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, stem cell regulation and tissue homeostasis. FZDs are linked to severe human pathology and are seen as a promising target for therapy. Despite intense efforts, no small molecule drugs with distinct efficacy have emerged. Here, we identify the Smoothened agonist SAG1.3 as a partial agonist of FZD(6) with limited subtype selectivity. Employing extensive in silico analysis, resonance energy transfer- and luciferase-based assays we describe the mode of action of SAG1.3. We define the ability of SAG1.3 to bind to FZD(6) and to induce conformational changes in the receptor, recruitment and activation of G proteins and dynamics in FZD-Dishevelled interaction. Our results provide the proof-of-principle that FZDs are targetable by small molecules acting on their seven transmembrane spanning core. Thus, we provide a starting point for a structure-guided and mechanism-based drug discovery process to exploit the potential of FZDs as therapeutic targets.