Conformational heterogeneity of the allosteric drug and metabolite (ADaM) site in AMP-activated protein kinase (AMPK)
文献类型：期刊论文
| 作者 | Gu, Xin4; Bridges, Michael D.2,3; Yan, Yan1,4; de Waal, Parker W.4; Zhou, X. Edward4; Suino-Powell, Kelly M.4; Xu, H. Eric1,4 ; Hubbell, Wayne L.2,3; Melcher, Karsten4
|
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2018-11-02 |
| 卷号 | 293期号:44页码:16994-17007 |
| 关键词 | AMP-activated kinase (AMPK) biophysics diabetes metabolic regulation cancer ADaM site DEER |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.RA118.004101 |
| 文献子类 | Article |
| 英文摘要 | AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and a promising drug target for managing metabolic diseases such as type 2 diabetes. Many pharmacological AMPK activators, and possibly unidentified physiological metabolites, bind to the allosteric drug and metabolite (ADaM) site at the interface between the kinase domain (KD) in the -subunit and the carbohydrate-binding module (CBM) in the -subunit. Here, using double electron-electron resonance (DEER) spectroscopy, we demonstrate that the CBM-KD interaction is partially dissociated and the interface highly disordered in the absence of pharmacological ADaM site activators as inferred from a low depth of modulation and broad DEER distance distributions. ADaM site ligands such as 991, and to a lesser degree phosphorylation, stabilize the KD-CBM association and strikingly reduce conformational heterogeneity in the ADaM site. Our findings that the ADaM site, formed by the KD-CBM interaction, can be modulated by diverse ligands and by phosphorylation suggest that it may function as a hub for integrating regulatory signals. |
| WOS关键词 | GAMMA-SUBUNIT ISOFORMS ; STRUCTURAL BASIS ; SKELETAL-MUSCLE ; ENERGY SENSOR ; GLYCOGEN ; BINDING ; MECHANISM ; A-769662 ; PHOSPHORYLATION ; HOMEOSTASIS |
| 资助项目 | Jules Stein Professorship Endowment[00000000] ; Van Andel Research Institute[00000000] ; National Institutes of Health[R01 GM102545] ; National Institutes of Health[R01 GM129436] ; National Institutes of Health[R01 EY05216] ; National Institutes of Health[T33 EY07026] ; National Institutes of Health[5P41EB001980] ; National Institutes of Health[R01 DK071662] ; National Natural Science Foundation of China[31300245] ; Ministry of Science and Technology (China)[2012ZX09301001] ; Ministry of Science and Technology (China)[2012CB910403] ; Ministry of Science and Technology (China)[2013CB910600] ; Ministry of Science and Technology (China)[XDB08020303] ; Ministry of Science and Technology (China)[2013ZX09507001] ; Amway (China)[00000000] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000449466500004 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279500]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Melcher, Karsten |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, VARI SIMM Ctr,Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China 2.Univ Calif Los Angeles, UCLA Sch Med, Dept Chem & Biochem, Los Angeles, CA 90095 USA; 3.Univ Calif Los Angeles, UCLA Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA; 4.Van Andel Res Inst, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA; |
| 推荐引用方式 GB/T 7714 | Gu, Xin,Bridges, Michael D.,Yan, Yan,et al. Conformational heterogeneity of the allosteric drug and metabolite (ADaM) site in AMP-activated protein kinase (AMPK)[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2018,293(44):16994-17007. |
| APA | Gu, Xin.,Bridges, Michael D..,Yan, Yan.,de Waal, Parker W..,Zhou, X. Edward.,...&Melcher, Karsten.(2018).Conformational heterogeneity of the allosteric drug and metabolite (ADaM) site in AMP-activated protein kinase (AMPK).JOURNAL OF BIOLOGICAL CHEMISTRY,293(44),16994-17007. |
| MLA | Gu, Xin,et al."Conformational heterogeneity of the allosteric drug and metabolite (ADaM) site in AMP-activated protein kinase (AMPK)".JOURNAL OF BIOLOGICAL CHEMISTRY 293.44(2018):16994-17007. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。