Details

Autor(en) / Beteiligte

• Langendorf, Christopher G.
• Ngoei, Kevin R. W.
• Scott, John W.
• Ling, Naomi X. Y.
• Issa, Sam M. A.
• Gorman, Michael A.
• Parker, Michael W.
• Sakamoto, Kei
• Oakhill, Jonathan S.
• Kemp, Bruce E.

Titel

Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding

Ist Teil von

• Nature communications, 2016-03, Vol.7 (1), p.10912-10912, Article 10912

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2016

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. AMPK regulates the metabolism and so drugs that activate AMPK might have potential for the treatment of metabolic disease. Here, the authors report the structure of AMPK bound to an activating compound, revealing two binding sites and indicating that dual therapy might be a good drug strategy.