The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose “importagog” to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated α2β2γ1 and α2β1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4′-nitrogen and β2-Asp111, which provide a design paradigm for β2-AMPK therapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2-AMPK therapeutics.

中文翻译：

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葡萄糖Importagog SC4激活骨骼肌AMPKα2β2γ1小分子的结构决定因素。

AMP激活的蛋白激酶（AMPK）αβγ异三聚体通过组织特异性同工型分布调节细胞能量稳态。骨骼肌α2β2AMPK复合物的小分子活化可能证明是治疗2型糖尿病和胰岛素抵抗的一种有价值的治疗策略。在本文中，我们报道了小分子SC4是有效的直接AMPK激活剂，可优先激活α2复合物并刺激骨骼肌葡萄糖摄取。与术语secretagog并行，我们提出“ importagog”来定义一种物质，该物质诱导或增加细胞对另一种物质的摄取。与活化的α2β2γ1和α2β1γ1配合物结合的葡萄糖导入物SC4的三维结构揭示了结合决定因素，特别是SC4咪唑并吡啶4'-氮与β2-Asp111之间的关键相互作用，提供了β2-AMPK治疗药物的设计范例。α2β2γ1/ SC4结构揭示了β2N端α螺旋与α2自抑制域之间的相互作用。我们的结果提供了结构功能指南，可加快有效但重要的组织特异性β2-AMPK治疗药物的开发。