Structural basis of AMPK regulation by small molecule activators.
Structural basis of AMPK regulation by small molecule activators.
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DOI：
10.1038/ncomms4017
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发表时间：
2013
影响因子：
16.6
通讯作者：
Gamblin, Steven J.
中科院分区：
文献类型：
--
作者：
Xiao, Bing;Sanders, Matthew J.;Carmena, David;Bright, Nicola J.;Haire, Lesley F.;Underwood, Elizabeth;Patel, Bhakti R.;Heath, Richard B.;Walker, Philip A.;Hallen, Stefan;Giordanetto, Fabrizio;Martin, Stephen R.;Carling, David;Gamblin, Steven J.
AMP激活的蛋白激酶（AMPK）通过感知和响应AMP/ADP浓度相对于ATP的增加而在调节细胞能量平衡中起主要作用。AMP的结合引起酶的变构活化，AMP或ADP的结合促进并维持激酶活化环内苏氨酸172的磷酸化。AMPK作为代谢性疾病（包括2型糖尿病和最近的癌症）的潜在治疗靶点引起了广泛的兴趣。已经报道了许多直接AMPK激活剂在治疗代谢疾病中具有有益作用，但是激活剂与AMPK结合没有结构基础。在这里，我们提出了人类AMPK的晶体结构与小分子激活剂的复合物，该小分子激活剂在激酶结构域和碳水化合物结合模块之间的位点结合，稳定这两个组件之间的相互作用。激活剂结合口袋的性质表明参与了一个额外的，尚未确定的，代谢产物在AMPK的生理调节。重要的是，该结构为设计用于治疗代谢紊乱的AMPK小分子活化剂提供了新的机会。 能量敏感激酶AMPK的小分子活化剂是治疗代谢性疾病的有希望的候选者。Xiao等人提出了AMPK与小分子激活剂复合的晶体结构，并表明该药物稳定了催化和碳水化合物结合结构域之间的相互作用。
AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders. Small molecule activators of the energy sensing kinase AMPK are promising candidates as therapies for metabolic disease. Xiao et al. present the crystal structure of AMPK in complex with a small molecule activator, and show that the drug stabilizes interaction between the catalytic and carbohydrate-binding domains.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1126/science.1215327
发表时间：
2012-05-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hawley SA;Fullerton MD;Ross FA;Schertzer JD;Chevtzoff C;Walker KJ;Peggie MW;Zibrova D;Green KA;Mustard KJ;Kemp BE;Sakamoto K;Steinberg GR;Hardie DG
通讯作者：
Hardie DG
影响因子：
9.2
作者：
Hudson, ER;Pan, DA;Hardie, DG
通讯作者：
Hardie, DG
影响因子：
4.1
作者：
Cheung, PCF;Salt, IP;Carling, D
通讯作者：
Carling, D