6C9F

AMP-activated protein kinase bound to pharmacological activator R734

Summary for 6C9F

• Entry DOI: 10.2210/pdb6c9f/pdb
• Descriptor: 5'-AMP-activated protein kinase catalytic subunit alpha-1,5'-AMP-activated protein kinase catalytic subunit alpha-1, 5'-AMP-activated protein kinase subunit beta-1, 5'-AMP-activated protein kinase subunit gamma-1, ... (6 entities in total)
• Functional Keywords: ampk, activator, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 119898.31

Authors

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. (deposition date: 2018-01-26, release date: 2018-11-28, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.924 Å)