Mechanism of action of compound-13: An α1-selective small molecule activator of AMPK
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Summary AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.
Originalsprog | Engelsk |
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Tidsskrift | Chemistry and Biology |
Vol/bind | 21 |
Udgave nummer | 7 |
Sider (fra-til) | 866-879 |
Antal sider | 14 |
ISSN | 1074-5521 |
DOI | |
Status | Udgivet - 17 jul. 2014 |
Eksternt udgivet | Ja |
ID: 239213236