Download MendeleyA conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation.
Littler, D.R., Walker, J.R., Davis, T., Wybenga-Groot, L.E., Finerty, P.J., Newman, E., Mackenzie, F., Dhe-Paganon, S.(2010) Acta Crystallogr Sect F Struct Biol Cryst Commun 66: 143-151
- PubMed: 20124709
- DOI: https://doi.org/10.1107/S1744309109052543
- Primary Citation of Related Structures:
2H6D - PubMed Abstract:
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 A resolution crystal structure of the isolated kinase domain from the alpha2 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 AMPKalpha2 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.
Organizational Affiliation:
The Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada. dene@phys.unsw.edu.au
