Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2ß2γ1 by the Glucose Importagog SC4.
Cell Chem Biol
; 25(6): 728-737.e9, 2018 06 21.
Article
en En
| MEDLINE
| ID: mdl-29657085
ABSTRACT
The AMP-activated protein kinase (AMPK) αßγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2ß2 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 α2ß2γ1 and α2ß1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and ß2-Asp111, which provide a design paradigm for ß2-AMPK therapeutics. The α2ß2γ1/SC4 structure reveals an interaction between a ß2 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, ß2-AMPK therapeutics.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Piridinas
/
Benzoatos
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Músculo Esquelético
/
Bibliotecas de Moléculas Pequeñas
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Proteínas Quinasas Activadas por AMP
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Glucosa
Límite:
Animals
Idioma:
En
Revista:
Cell Chem Biol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Australia