Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states
文献类型：期刊论文
| 作者 | Yan, Yan1,2,3; Zhou, X. Edward1; Novick, Scott J.4; Shaw, Simon J.5; Li, Yingwu5; Brunzelle, Joseph S.6; Hitoshi, Yasumichi5; Griffin, Patrick R.4; Xu, H. Eric1,2 ; Melcher, Karsten1
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| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
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| 出版日期 | 2019-01-18 |
| 卷号 | 294期号:3页码:953-967 |
| 关键词 | AMP-activated kinase (AMPK) AMP hydrogen exchange mass spectrometry X-ray crystallography phosphorylation activation loop phosphorylation ADaM site CBS3 R734 R739 metabolic disorder energy sensor |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.RA118.004883 |
| 通讯作者 | Melcher, Karsten(karsten.melcher@vai.org) |
| 英文摘要 | AMP-activated protein kinase (AMPK) is an attractive therapeutic target for managing metabolic diseases. A class of pharmacological activators, including Merck 991, binds the AMPK ADaM site, which forms the interaction surface between the kinase domain (KD) of the alpha-subunit and the carbohydrate-binding module (CBM) of the beta-subunit. Here, we report the development of two new 991-derivative compounds, R734 and R739, which potently activate AMPK in a variety of cell types, including beta(2)-specific skeletal muscle cells. Surprisingly, we found that they have only minor effects on direct kinase activity of the recombinant alpha(1)beta(2)gamma(1) isoform yet robustly enhance protection against activation loop dephosphorylation. This mode of activation is reminiscent of that of ADP, which activates AMPK by binding to the nucleotide-binding sites in the gamma-subunit, more than 60 A away from the ADaM site. To understand the mechanisms of full and partial AMPK activation, we determined the crystal structures of fully active phosphorylated AMPK alpha(1)beta(1)gamma(1) bound to AMP and R734/R739 as well as partially active nonphosphorylated AMPK bound to R734 and AMP and phosphorylated AMPK bound to R734 in the absence of added nucleotides at <3-A resolution. These structures and associated analyses identified a novel conformational state of the AMPK autoinhibitory domain associated with partial kinase activity and provide new insights into phosphorylation-dependent activation loop stabilization in AMPK. |
| WOS关键词 | GAMMA-SUBUNIT ISOFORMS ; UPSTREAM KINASE ; ENERGY SENSOR ; METFORMIN ; MECHANISM ; DRUGS ; BETA ; IDENTIFICATION ; HEPATOCYTES ; A-769662 |
| 资助项目 | Van Andel Research Institute ; National Institutes of Health[R01 GM102545] ; National Institutes of Health[R01 GM129436] ; National Institutes of Health[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) |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000458670200020 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/290502]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Melcher, Karsten |
| 作者单位 | 1.Van Andel Res Inst, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA 2.Chinese Acad Sci, Shanghai Inst Materia Med VARI SIMM Ctr, Shanghai Inst Materia Med,CAS Key Lab Receptor Re, Ctr Struct & Funct Drug Targets,Van Andel Res Ins, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Scripps Res Inst, Scripps Florida, Dept Mol Med, Jupiter, FL 33458 USA 5.Rigel Pharmaceut Inc, San Francisco, CA 94080 USA 6.Northwestern Univ, Life Sci Collaborat Access Team, Synchrotron Res Ctr, Argonne, IL 60439 USA |
| 推荐引用方式 GB/T 7714 | Yan, Yan,Zhou, X. Edward,Novick, Scott J.,et al. Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2019,294(3):953-967. |
| APA | Yan, Yan.,Zhou, X. Edward.,Novick, Scott J..,Shaw, Simon J..,Li, Yingwu.,...&Melcher, Karsten.(2019).Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states.JOURNAL OF BIOLOGICAL CHEMISTRY,294(3),953-967. |
| MLA | Yan, Yan,et al."Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states".JOURNAL OF BIOLOGICAL CHEMISTRY 294.3(2019):953-967. |
入库方式： OAI收割
来源：上海药物研究所
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