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

AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and a promising drug target for managing metabolic diseases such as type 2 diabetes. Many pharmacological AMPK activators, and possibly unidentified physiological metabolites, bind to the allosteric drug and metabolite (...

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Bibliographic Details
Published in:The Journal of biological chemistry 2018-11, Vol.293 (44), p.16994-17007
Main Authors: Gu, Xin, Bridges, Michael D., Yan, Yan, de Waal, Parker W., Zhou, X. Edward, Suino-Powell, Kelly M., Xu, H. Eric, Hubbell, Wayne L., Melcher, Karsten
Format: Article
Language:English
Subjects:
Adenosine Monophosphate - chemistry
Adenosine Monophosphate - metabolism
Allosteric Regulation
AMP-Activated Protein Kinases - chemistry
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
Benzimidazoles - chemistry
Benzimidazoles - metabolism
Benzoates - chemistry
Benzoates - metabolism
Binding Sites
Catalytic Domain
Crystallography, X-Ray
Humans
Ligands
Molecular Biophysics
Protein Conformation
Protein Domains
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Summary:AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and a promising drug target for managing metabolic diseases such as type 2 diabetes. Many pharmacological AMPK activators, and possibly unidentified physiological metabolites, bind to the allosteric drug and metabolite (ADaM) site at the interface between the kinase domain (KD) in the α-subunit and the carbohydrate-binding module (CBM) in the β-subunit. Here, using double electron–electron resonance (DEER) spectroscopy, we demonstrate that the CBM–KD interaction is partially dissociated and the interface highly disordered in the absence of pharmacological ADaM site activators as inferred from a low depth of modulation and broad DEER distance distributions. ADaM site ligands such as 991, and to a lesser degree phosphorylation, stabilize the KD–CBM association and strikingly reduce conformational heterogeneity in the ADaM site. Our findings that the ADaM site, formed by the KD–CBM interaction, can be modulated by diverse ligands and by phosphorylation suggest that it may function as a hub for integrating regulatory signals.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA118.004101