AMP-activated protein kinase beta subunit carbohydrate-binding module (AMPK beta-CBM) (AMPK beta-CBM)

The AMP-activated protein kinase (AMPK) beta subunit carbohydrate-binding module (CBM) is a specialized regulatory domain within the AMPK heterotrimer, which serves as a central sensor of cellular energy status [1, 2]. Belonging to the CBM20 family, this module is primarily responsible for binding glycogen, which localizes the AMPK complex to glycogen particles and allows it to sense carbohydrate availability [5]. Beyond its role in glycogen sensing, the CBM is a critical component of the Allosteric Drug and Metabolite (ADaM) site, a pocket formed at the interface between the beta subunit CBM and the alpha subunit kinase domain [3]. This site is the target for several direct small-molecule activators, such as A-769662 and MK-8722, which bind to the CBM to allosterically activate the enzyme and protect it from dephosphorylation [3, 4]. Pharmacological targeting of the AMPK beta-CBM is a major strategy for treating metabolic disorders like type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) by promoting glucose uptake and lipid oxidation [4, 5]. However, chronic activation via this site has been associated with safety concerns such as cardiac hypertrophy in preclinical models, posing a challenge for clinical development [4].

Other names

Glycogen-binding domainGBDCBM20 domain of AMPKAMPK beta-1 CBMAMPK beta-2 CBMADaM site (component)

Allosteric activation of the AMPK heterotrimer by binding to the Allosteric Drug and Metabolite (ADaM) site at the interface of the alpha and beta subunits, which stabilizes the active conformation and inhibits dephosphorylation of the activation loop.