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Structural insight into small molecule action on Frizzleds.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-21 , DOI: 10.1038/s41467-019-14149-3
Paweł Kozielewicz 1 , Ainoleena Turku 1 , Carl-Fredrik Bowin 1 , Julian Petersen 1 , Jana Valnohova 1 , Maria Consuelo Alonso Cañizal 2, 3 , Yuki Ono 4 , Asuka Inoue 4 , Carsten Hoffmann 2, 3 , Gunnar Schulte 1
Affiliation  

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 FZD6 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 FZD6 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.

中文翻译:

对小分子在卷曲蛋白上的作用的结构见解。

WNT-Frizzled(FZD)信号在胚胎发育,干细胞调节和组织体内平衡中起着至关重要的作用。FZD与严重的人类病理相关,被视为治疗的有希望的靶标。尽管付出了巨大的努力,但尚未出现具有独特功效的小分子药物。在这里,我们确定平滑化激动剂SAG1.3为FZD6的部分激动剂,亚型选择性有限。通过广泛的计算机分析,基于共振能量转移和荧光素酶的分析方法,我们描述了SAG1.3的作用方式。我们定义了SAG1.3与FZD6结合并诱导受体构象变化,G蛋白募集和激活以及FZD杂散相互作用动力学的能力。我们的结果提供了原理证明,FZD可被作用于其七个跨膜跨核的小分子靶向。因此,我们为结构指导和基于机制的药物发现过程提供了起点,以利用FZD作为治疗靶标的潜力。
更新日期:2020-01-22
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