Structural basis of AMPK regulation by adenine nucleotides and glycogen.
Structural basis of AMPK regulation by adenine nucleotides and glycogen.
复制标题
腺嘌呤核苷酸和糖原调节 AMPK 的结构基础。
DOI：
10.1038/cr.2014.150
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发表时间：
2015-01
期刊：
影响因子：
44.1
通讯作者：
Melcher K
中科院分区：
文献类型：
--
作者：
Li X;Wang L;Zhou XE;Ke J;de Waal PW;Gu X;Tan MH;Wang D;Wu D;Xu HE;Melcher K
AMP活化蛋白激酶（AMPK）是一种重要的细胞能量传感器和能量稳态调节因子，是治疗糖尿病、肥胖和癌症的药物靶点。在这里，我们呈现了与其变构调节剂AMP和糖原模拟环糊精结合的人α1β2γ1全AMPK复合物的低分辨率晶体结构，磷酸化（4.05 μ M）和非磷酸化（4.60 μ M）状态。此外，我们已经解决了一个2.95 kb的结构的人激酶结构域（KD）结合到相邻的自抑制结构域（AID），并进行了广泛的生化和突变的研究。总之，这些研究说明了AMP和糖原的变构AMPK调节的潜在机制，其结合改变了交替AID（AMP）和碳水化合物结合模块（糖原）相互作用之间的平衡。
AMP-activated protein kinase (AMPK) is a central cellular energy sensor and regulator of energy homeostasis, and a promising drug target for the treatment of diabetes, obesity, and cancer. Here we present low-resolution crystal structures of the human α1β2γ1 holo-AMPK complex bound to its allosteric modulators AMP and the glycogen-mimic cyclodextrin, both in the phosphorylated (4.05 Å) and non-phosphorylated (4.60 Å) state. In addition, we have solved a 2.95 Å structure of the human kinase domain (KD) bound to the adjacent autoinhibitory domain (AID) and have performed extensive biochemical and mutational studies. Together, these studies illustrate an underlying mechanism of allosteric AMPK modulation by AMP and glycogen, whose binding changes the equilibria between alternate AID (AMP) and carbohydrate-binding module (glycogen) interactions.