9IC2

Structure of AMPK-alpha2-kinase domain bound to BAY-3827

This is a non-PDB format compatible entry.

Summary for 9IC2

• Entry DOI: 10.2210/pdb9ic2/pdb
• Descriptor: 5'-AMP-activated protein kinase catalytic subunit alpha-2, ~{N}-[5-(3,5-dicyano-1,2,6-trimethyl-4~{H}-pyridin-4-yl)-6-fluoranyl-7-methyl-1~{H}-indazol-3-yl]-2-ethyl-benzamide, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kinase, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32223.26

Authors

Ahangar, M.S.,Zeqiraj, E.,Fraguas Bringas, C.,Sakamoto, K. (deposition date: 2025-02-14, release date: 2025-09-03, Last modification date: 2026-03-18)

Primary citation

Fraguas Bringas, C.,Ahangar, M.S.,Cuenco, J.,Liu, H.,Addinsall, A.B.,Lindahl, M.,Ovens, A.J.,Febbraio, M.A.,Foretz, M.,Goransson, O.,Scott, J.W.,Zeqiraj, E.,Sakamoto, K.
Mechanism and cellular actions of the potent AMPK inhibitor BAY-3827.
Sci Adv, 11:eadx2434-eadx2434, 2025

PubMed Abstract: Inhibition of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is under increasing investigation for its therapeutic potential in many diseases. Existing AMPK inhibitors are however limited, with poor selectivity and substantial off-target effects. Here, we provide mechanistic insights and describe the cellular selectivity of the recently identified AMPK inhibitor BAY-3827. A 2.5-Å cocrystal structure of the AMPK kinase domain with BAY-3827 revealed distinct features including a disulfide bridge between the αD helix Cys and the activation loop residue Cys. This bridge appears to stabilize the activation loop such that Asn repositions the Asp-Phe-Gly (DFG) motif Phe toward the C-terminal lobe, displacing His and disrupting the regulatory spine, promoting an inactive kinase state. In hepatocytes, BAY-3827 blocked AMPK activator (MK-8722)-mediated phosphorylation of ACC1 and corresponding inhibition of lipogenesis. Transcriptome analysis revealed that BAY-3827 down-regulated ~30% of MK-8722-stimulated AMPK-dependent genes. We establish the molecular and cellular basis of BAY-3827's selectivity and utility for delineating AMPK functions while highlighting its limitations.

PubMed: 40845097
DOI: 10.1126/sciadv.adx2434

Experimental method

X-RAY DIFFRACTION (2.5 Å)