Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4
Journal article
Ngoei, Kevin R.W., Langendorf, Christopher G., Ling, Naomi, Hoque, Ashfaqul, Johnson, Swapna, Camerino, Michelle C., Walker, Scott R., Bozikis, Ylva E., Dite, Toby A., Ovens, Ashley J., Smiles, William, Jacobs, Roxane, Huang, He, Parker, Michael W., Scott, John W., Rider, Mark H., Foitzik, Richard C., Kemp, Bruce, Baell, Jonathan B. and Oakhill, Jonathan S.. (2018). Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4. Cell Chemical Biology. 25(6), pp. 728 - 737. https://doi.org/10.1016/j.chembiol.2018.03.008
Authors | Ngoei, Kevin R.W., Langendorf, Christopher G., Ling, Naomi, Hoque, Ashfaqul, Johnson, Swapna, Camerino, Michelle C., Walker, Scott R., Bozikis, Ylva E., Dite, Toby A., Ovens, Ashley J., Smiles, William, Jacobs, Roxane, Huang, He, Parker, Michael W., Scott, John W., Rider, Mark H., Foitzik, Richard C., Kemp, Bruce, Baell, Jonathan B. and Oakhill, Jonathan S. |
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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 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4′-nitrogen and β2-Asp111, which provide a design paradigm for β2-AMPK therapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2-AMPK therapeutics. Therapeutic activation of the metabolic regulator AMPK in skeletal muscle is a validated strategy to combat type 2 diabetes. Ngoei et al. have solved the crystal structure of the activator SC4complexed to a skeletal muscle AMPK isoform, identifying important binding determinants that will advance development of AMPK-targeting therapeutics. |
Keywords | AMP-activated protein kinases; diabetes; drug development; glucose disposal; importagog; metabolism; secretagog; X-ray crystallography |
Year | 2018 |
Journal | Cell Chemical Biology |
Journal citation | 25 (6), pp. 728 - 737 |
Publisher | Cell Press |
ISSN | 2451-9448 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.chembiol.2018.03.008 |
Scopus EID | 2-s2.0-85045001016 |
Page range | 728 - 737 |
Research Group | Mary MacKillop Institute for Health Research |
Publisher's version | File Access Level Controlled |
Place of publication | United Kingdom |
Editors | C. M. Crews and K. Shokat |
https://acuresearchbank.acu.edu.au/item/8822x/structural-determinants-for-small-molecule-activation-of-skeletal-muscle-ampk-2-2-1-by-the-glucose-importagog-sc4
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