5EZV

X-ray crystal structure of AMP-activated protein kinase alpha-2/alpha-1 RIM chimaera (alpha-2(1-347)/alpha-1(349-401)/alpha-2(397-end) beta-1 gamma-1) co-crystallized with C2 (5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid)

Summary for 5EZV

• Entry DOI: 10.2210/pdb5ezv/pdb
• Descriptor: 5'-AMP-activated protein kinase catalytic subunit alpha-2/alpha-1 RIM SWAP chimera, 5'-AMP-activated protein kinase subunit beta-1, 5'-AMP-activated protein kinase subunit gamma-1, ... (7 entities in total)
• Functional Keywords: transferase, serine/threonine kinase, allosteric activation, nucleotide-binding
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : P54646
• Total number of polymer chains: 6
• Total formula weight: 267844.05

Authors

Langendorf, C.G.,Kemp, B.E. (deposition date: 2015-11-26, release date: 2016-03-09, Last modification date: 2024-11-13)

Primary citation

Langendorf, C.G.,Ngoei, K.R.,Scott, J.W.,Ling, N.X.,Issa, S.M.,Gorman, M.A.,Parker, M.W.,Sakamoto, K.,Oakhill, J.S.,Kemp, B.E.
Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding.
Nat Commun, 7:10912-10912, 2016

PubMed Abstract: The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.

PubMed: 26952388
DOI: 10.1038/ncomms10912

Experimental method

X-RAY DIFFRACTION (2.99 Å)