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

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.

AMP-activated protein kinase: the current landscape for drug development

“…26 ). Using a recently identified activator, SC4, it was shown that Asp111 in β2 interacts with the imidazopyridine 4ʹ-nitrogen of the compound, which could provide increased stabilization of binding to β2-containing AMPK complexes 176 . The availability of pan-β activators in addition to highly selective β1 activators has provided a useful tool for investigating β isoform-specific effects in vivo.…”

AMP-Activated Protein Kinase and Host Defense against Infection

“…The beneficial effects of these compounds remain to be fully determined. Thus, selective compounds such as MK-8722 [ 98 ] and SC4 [ 99 ] and the selective inhibitor SBI-0206965 [ 100 ] should be considered for future AMPK-targeted treatment strategies.…”

Conformational heterogeneity of the allosteric drug and metabolite (ADaM) site in AMP-activated protein kinase (AMPK)

“…Given the high potential of the ADaM site for the design of AMPK-activating therapeutics, as well as its potential as binding pocket for hypothesized, novel physiological AMPK regulators, it is important to understand its conformational landscape and dynamics. Currently, only one crystal structure of an ADaM site ligand bound to a ␤ 2 -containing AMPK complex has been determined (26), which represents a single conformation snapshot. In contrast, biochemical characterization suggests that different ligands and different ␤ subunits induce different AMPK activity states.…”