2. Academic Validation
  3. Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4

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

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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