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Title: Structural basis of AMPK regulation by adenine nucleotides and glycogen

AMP-activated protein kinase (AMPK) is a central cellular energy sensor and regulator of energy homeostasis, and a promising drug target for the treatment of diabetes, obesity, and cancer. Here we present low-resolution crystal structures of the human α1β2γ1 holo-AMPK complex bound to its allosteric modulators AMP and the glycogen-mimic cyclodextrin, both in the phosphorylated (4.05 Å) and non-phosphorylated (4.60 Å) state. In addition, we have solved a 2.95 Å structure of the human kinase domain (KD) bound to the adjacent autoinhibitory domain (AID) and have performed extensive biochemical and mutational studies. Altogether, these studies illustrate an underlying mechanism of allosteric AMPK modulation by AMP and glycogen, whose binding changes the equilibria between alternate AID (AMP) and carbohydrate-binding module (glycogen) interactions.
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [3] ;  [4] ;  [4] ;  [5] ;  [2]
  1. Chinese Academy of Sciences, Guangdong (China); Univ. of Science and Technology of China, Anhui (China); Van Andel Research Institute, Grand Rapids, MI (United States)
  2. Van Andel Research Institute, Grand Rapids, MI (United States)
  3. Van Andel Research Institute, Grand Rapids, MI (United States); National Univ. of Singapore (Singapore)
  4. Chinese Academy of Sciences, Guangdong (China)
  5. Van Andel Research Institute, Grand Rapids, MI (United States); Chinese Academy of Sciences, Shanghai (China)
Publication Date:
OSTI Identifier:
1169343
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Cell Research
Additional Journal Information:
Journal Volume: 25; Journal Issue: 1; Journal ID: ISSN 1001-0602
Publisher:
Shanghai Institutes for Biological Sciences
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES AMPK; adenine nucleotides; glycogen; diabetes