title: Structural basis of AMPK regulation by adenine nucleotides and glycogen.
abstract: 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. Together, 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.affiliation: 1] Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China [2] School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China [3] Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Li
authors.affiliation: 1] Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China [2] School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China [3] Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Ke
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
authors.forename: Parker W
authors.initials: PW
authors.lastname: de Waal
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
authors.affiliation: 1] Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA [2] Department of Obstetrics & Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore, 119074, Singapore.
authors.forename: M H Eileen
authors.initials: MH
authors.lastname: Tan
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
authors.forename: Dongye
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.affiliation: 1] Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA [2] VARI/SIMM Center, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation; D018360:Crystallography, X-Ray; D003505:Cyclodextrins / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
chemical_list: D003505:Cyclodextrins; D021122:Protein Subunits; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D006003:Glycogen; D055372:AMP-Activated Protein Kinases