Journal article
Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4
KRW Ngoei, CG Langendorf, NXY Ling, A Hoque, S Varghese, MA Camerino, SR Walker, YE Bozikis, TA Dite, AJ Ovens, WJ Smiles, R Jacobs, H Huang, MW Parker, JW Scott, MH Rider, RC Foitzik, BE Kemp, JB Baell, JS Oakhill
Cell Chemical Biology | CELL PRESS | Published : 2018
Abstract
The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose “importagog” to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated α2β2γ1 and α2β1γ1 comp..
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Awarded by Jack Brockhoff Foundation
Funding Acknowledgements
This research was undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia, part of ANSTO, and made use of the ACRF detector. We thank the beamline staff for their assistance. We thank Sandra Galic and Lisa Murray-Segal for assistance with preparation of primary hepatocytes and isolation of mouse muscles. This work was supported by grants from the Australian Research Council (ARC ID: 130100988) and the National Health and Medical Research Council (NHMRC ID: 1098459, 1145265). C.G.L. is an EH Flack Fellow and is supported by the Jack Brockhoff foundation (JBF-4206, 2016). M.W.P., B.E.K., and J.B.B. are NHMRC Research Fellows. J.S.O. is an ARC Future Fellow. This study was supported in part by the Victorian Government's Operational Infrastructure Support Program.