Li Xiaodan, Wang Lili, Zhou X Edward, Ke Jiyuan, de Waal Parker W, Gu Xin, Tan M H Eileen, Wang Dongye, Wu Donghai, Xu H Eric, Melcher Karsten
1] Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China [2] School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China [3] Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
Cell Res. 2015 Jan;25(1):50-66. doi: 10.1038/cr.2014.150. Epub 2014 Nov 21.
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.
AMP激活的蛋白激酶（AMPK）是细胞能量的核心传感器和能量稳态的调节因子，也是治疗糖尿病、肥胖症和癌症的一个很有前景的药物靶点。在此，我们展示了人α1β2γ1全酶AMPK复合物与变构调节剂AMP和糖原模拟环糊精结合的低分辨率晶体结构，二者分别处于磷酸化（4.05 Å）和非磷酸化（4.60 Å）状态。此外，我们解析了人激酶结构域（KD）与相邻的自身抑制结构域（AID）结合的2.95 Å结构，并进行了广泛的生化和突变研究。这些研究共同阐明了AMP和糖原对AMPK变构调节的潜在机制，其结合改变了交替的AID（AMP）和碳水化合物结合模块（糖原）相互作用之间的平衡。
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