7JHG

Cryo-EM structure of ATP-bound fully inactive AMPK in complex with Dorsomorphin (Compound C) and Fab-nanobody

Summary for 7JHG

• Entry DOI: 10.2210/pdb7jhg/pdb
• Related: 7JHH
• EMDB information: 22336 22337
• Related PRD ID: PRD_900001
• Descriptor: 5'-AMP-activated protein kinase catalytic subunit alpha-1, ADENOSINE-5'-TRIPHOSPHATE, ADENOSINE-5'-DIPHOSPHATE, ... (12 entities in total)
• Functional Keywords: ampk, atp, fully inactive, kd-displaced, transferase-immune system complex, transferase/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 7
• Total formula weight: 222183.50

Authors

Yan, Y.,Murkherjee, S.,Zhou, X.E.,Xu, T.H.,Xu, H.E.,Kossiakoff, A.A.,Melcher, K. (deposition date: 2020-07-20, release date: 2021-07-21, Last modification date: 2021-12-15)

Primary citation

Yan, Y.,Mukherjee, S.,Harikumar, K.G.,Strutzenberg, T.S.,Zhou, X.E.,Suino-Powell, K.,Xu, T.H.,Sheldon, R.D.,Lamp, J.,Brunzelle, J.S.,Radziwon, K.,Ellis, A.,Novick, S.J.,Vega, I.E.,Jones, R.G.,Miller, L.J.,Xu, H.E.,Griffin, P.R.,Kossiakoff, A.A.,Melcher, K.
Structure of an AMPK complex in an inactive, ATP-bound state.
Science, 373:413-419, 2021

PubMed Abstract: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under energy stress, AMP stabilizes the active AMPK conformation, in which the kinase activation loop (AL) is protected from protein phosphatases, thus keeping the AL in its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits AMPK by increasing AL dynamics and accessibility. We developed conformation-specific antibodies to trap ATP-bound AMPK in a fully inactive, dynamic state and determined its structure at 3.5-angstrom resolution using cryo-electron microscopy. A 180° rotation and 100-angstrom displacement of the kinase domain fully exposes the AL. On the basis of the structure and supporting biophysical data, we propose a multistep mechanism explaining how adenine nucleotides and pharmacological agonists modulate AMPK activity by altering AL phosphorylation and accessibility.

PubMed: 34437114
DOI: 10.1126/science.abe7565

Experimental method

ELECTRON MICROSCOPY (3.47 Å)