6C9H

non-phosphorylated AMP-activated protein kinase bound to pharmacological activator R734

6C9H の概要

• エントリーDOI: 10.2210/pdb6c9h/pdb
• 分子名称: 5'-AMP-activated protein kinase catalytic subunit alpha-1, 5'-AMP-activated protein kinase subunit beta-1, 5'-AMP-activated protein kinase subunit gamma-1, ... (7 entities in total)
• 機能のキーワード: ampk, activator, r734, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 119818.33

構造登録者

Yan, Y.,Zhou, X.E.,Novick, S.,Shaw, S.J.,Li, Y.,Hitoshi, Y.,Brunzelle, J.S.,Griffin, P.R.,Xu, H.E.,Melcher, K. (登録日: 2018-01-26, 公開日: 2018-11-28, 最終更新日: 2023-10-04)

主引用文献

Yan, Y.,Zhou, X.E.,Novick, S.J.,Shaw, S.J.,Li, Y.,Brunzelle, J.S.,Hitoshi, Y.,Griffin, P.R.,Xu, H.E.,Melcher, K.
Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states.
J. Biol. Chem., 294:953-967, 2019

PubMed Abstract: 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 α-subunit and the carbohydrate-binding module (CBM) of the β-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 β-specific skeletal muscle cells. Surprisingly, we found that they have only minor effects on direct kinase activity of the recombinant αβγ 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 γ-subunit, more than 60 Å 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 αβγ 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-Å 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.

PubMed: 30478170
DOI: 10.1074/jbc.RA118.004883

実験手法

X-RAY DIFFRACTION (2.65 Å)