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

Kevin R.W. Ngoei, Christopher G. Langendorf, Naomi X.Y. Ling, Ashfaqul Hoque, Swapna Varghese, Michelle A. Camerino, Scott R. Walker, Ylva E. Bozikis, Toby A. Dite, Ashley J. Ovens, William J. Smiles, Roxane Jacobs, He Huang, Michael W. Parker, John W. Scott, Mark H. Rider, Richard C. Foitzik, Bruce E. Kemp, Jonathan B. Baell, Jonathan S. Oakhill

Research output: Contribution to journalArticleResearchpeer-review

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 SC4 complexed to a skeletal muscle AMPK isoform, identifying important binding determinants that will advance development of AMPK-targeting therapeutics.

Original languageEnglish
Pages (from-to)728-737.e9
Number of pages20
JournalCell Chemical Biology
Volume25
Issue number6
DOIs
Publication statusPublished - 21 Jun 2018

Keywords

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

Cite this

Ngoei, Kevin R.W. ; Langendorf, Christopher G. ; Ling, Naomi X.Y. ; Hoque, Ashfaqul ; Varghese, Swapna ; Camerino, Michelle A. ; Walker, Scott R. ; Bozikis, Ylva E. ; Dite, Toby A. ; Ovens, Ashley J. ; Smiles, William J. ; Jacobs, Roxane ; Huang, He ; Parker, Michael W. ; Scott, John W. ; Rider, Mark H. ; Foitzik, Richard C. ; Kemp, Bruce E. ; Baell, Jonathan B. ; Oakhill, Jonathan S. / Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4. In: Cell Chemical Biology. 2018 ; Vol. 25, No. 6. pp. 728-737.e9.
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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 SC4 complexed to a skeletal muscle AMPK isoform, identifying important binding determinants that will advance development of AMPK-targeting therapeutics.",
keywords = "AMP-activated protein kinase, diabetes, drug development, glucose disposal, importagog, metabolism, secretagog, X-ray crystallography",
author = "Ngoei, {Kevin R.W.} and Langendorf, {Christopher G.} and Ling, {Naomi X.Y.} and Ashfaqul Hoque and Swapna Varghese and Camerino, {Michelle A.} and Walker, {Scott R.} and Bozikis, {Ylva E.} and Dite, {Toby A.} and Ovens, {Ashley J.} and Smiles, {William J.} and Roxane Jacobs and He Huang and Parker, {Michael W.} and Scott, {John W.} and Rider, {Mark H.} and Foitzik, {Richard C.} and Kemp, {Bruce E.} and Baell, {Jonathan B.} and Oakhill, {Jonathan S.}",
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month = "6",
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Ngoei, KRW, Langendorf, CG, Ling, NXY, Hoque, A, Varghese, S, Camerino, MA, Walker, SR, Bozikis, YE, Dite, TA, Ovens, AJ, Smiles, WJ, Jacobs, R, Huang, H, Parker, MW, Scott, JW, Rider, MH, Foitzik, RC, Kemp, BE, Baell, JB & Oakhill, JS 2018, 'Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4' Cell Chemical Biology, vol. 25, no. 6, pp. 728-737.e9. https://doi.org/10.1016/j.chembiol.2018.03.008

Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4. / Ngoei, Kevin R.W.; Langendorf, Christopher G.; Ling, Naomi X.Y.; Hoque, Ashfaqul; Varghese, Swapna; Camerino, Michelle A.; Walker, Scott R.; Bozikis, Ylva E.; Dite, Toby A.; Ovens, Ashley J.; Smiles, William J.; Jacobs, Roxane; Huang, He; Parker, Michael W.; Scott, John W.; Rider, Mark H.; Foitzik, Richard C.; Kemp, Bruce E.; Baell, Jonathan B.; Oakhill, Jonathan S.

In: Cell Chemical Biology, Vol. 25, No. 6, 21.06.2018, p. 728-737.e9.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Ngoei, Kevin R.W.

AU - Langendorf, Christopher G.

AU - Ling, Naomi X.Y.

AU - Hoque, Ashfaqul

AU - Varghese, Swapna

AU - Camerino, Michelle A.

AU - Walker, Scott R.

AU - Bozikis, Ylva E.

AU - Dite, Toby A.

AU - Ovens, Ashley J.

AU - Smiles, William J.

AU - Jacobs, Roxane

AU - Huang, He

AU - Parker, Michael W.

AU - Scott, John W.

AU - Rider, Mark H.

AU - Foitzik, Richard C.

AU - Kemp, Bruce E.

AU - Baell, Jonathan B.

AU - Oakhill, Jonathan S.

PY - 2018/6/21

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N2 - 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 SC4 complexed to a skeletal muscle AMPK isoform, identifying important binding determinants that will advance development of AMPK-targeting therapeutics.

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KW - AMP-activated protein kinase

KW - diabetes

KW - drug development

KW - glucose disposal

KW - importagog

KW - metabolism

KW - secretagog

KW - X-ray crystallography

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U2 - 10.1016/j.chembiol.2018.03.008

DO - 10.1016/j.chembiol.2018.03.008

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