A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation

作者：Littler Dene R^*; Walker John R; Davis Tara; Wybenga Groot Leanne E; Finerty Patrick J Jr; Newman Elena; Mackenzie Farell; Dhe Paganon Sirano

来源：Acta Crystallographica Section F-Structural Biology and Crystallization Communications, 2010, 66(2): 143-151.

DOI：10.1107/S1744309109052543

The AMP-activated protein kinase (AMPK) is a highly conserved trimeric protein complex that is responsible for energy homeostasis in eukaryotic cells. Here, a 1.9 angstrom resolution crystal structure of the isolated kinase domain from the alpha 2 subunit of human AMPK, the first from a multicellular organism, is presented. This human form adopts a catalytically inactive state with distorted ATP-binding and substrate-binding sites. The ATP site is affected by changes in the base of the activation loop, which has moved into an inhibited DFG-out conformation. The substrate-binding site is disturbed by changes within the AMPK alpha 2 catalytic loop that further distort the enzyme from a catalytically active form. Similar structural rearrangements have been observed in a yeast AMPK homologue in response to the binding of its auto-inhibitory domain; restructuring of the kinase catalytic loop is therefore a conserved feature of the AMPK protein family and is likely to represent an inhibitory mechanism that is utilized during function.

• 出版日期2010-2