Login / Signup

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

Xin GuMichael D BridgesYan YanParker W de WaalX Edward ZhouKelly M Suino-PowellH Eric XuWayne L HubbellKarsten Melcher
Published in: The Journal of biological chemistry (2018)
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.
Keyphrases
  • protein kinase
  • type diabetes
  • small molecule
  • molecular dynamics
  • transcription factor
  • cardiovascular disease
  • single cell
  • ms ms
  • skeletal muscle
  • adverse drug
  • drug induced