Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4

  • Cell Chem Biol. 2018 Jun 21;25(6):728-737.e9. doi: 10.1016/j.chembiol.2018.03.008.
Kevin R W Ngoei  1 ,  Christopher G Langendorf  2 ,  Naomi X Y Ling  3 ,  Ashfaqul Hoque  3 ,  Swapna Varghese  4 ,  Michelle A Camerino  5 ,  Scott R Walker  5 ,  Ylva E Bozikis  5 ,  Toby A Dite  3 ,  Ashley J Ovens  6 ,  William J Smiles  3 ,  Roxane Jacobs  7 ,  He Huang  8 ,  Michael W Parker  9 ,  John W Scott  10 ,  Mark H Rider  7 ,  Richard C Foitzik  11 ,  Bruce E Kemp  10 ,  Jonathan B Baell  12 ,  Jonathan S Oakhill  13
Affiliations
  • 1. Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia.
  • 2. Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia. Electronic address: [email protected].
  • 3. Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia.
  • 4. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 5. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx) Pty Ltd, Level 3, 343 Royal Parade, Parkville, VIC 3052, Australia.
  • 6. Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000, Australia.
  • 7. Université catholique de Louvain (UCL), de Duve Institute, Avenue Hippocrate 75 bte 74.02, 1200 Brussels, Belgium.
  • 8. Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
  • 9. ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3052, Australia.
  • 10. Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000, Australia.
  • 11. Cancer Therapeutics CRC (CTx) Pty Ltd, Level 3, 343 Royal Parade, Parkville, VIC 3052, Australia; MecRX Pty Ltd, Level 9, 31 Queen Street, Melbourne, VIC 3000, Australia.
  • 12. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
  • 13. Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000, Australia. Electronic address: [email protected].
PMID: 29657085 DOI: 10.1016/j.chembiol.2018.03.008
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.

Keywords
AMP-activated protein kinase; X-ray crystallography; diabetes; drug development; glucose disposal; importagog; metabolism; secretagog.
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