title: Structural basis for compound C inhibition of the human AMP-activated protein kinase α2 subunit kinase domain.
abstract: AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK α2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK α2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the `DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery.
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Handa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takagi
authors.forename: Shinya
authors.initials: S
authors.lastname: Saijo
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kishishita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takaya
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Toyama
authors.forename: Takaho
authors.initials: T
authors.lastname: Terada
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Suni
authors.initials: S
authors.lastname: Lee
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Miki
authors.initials: M
authors.lastname: Okada-Iwabu
authors.forename: Masato
authors.initials: M
authors.lastname: Iwabu
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology; D006801:Humans; D024821:Metabolic Syndrome / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D055372:AMP-Activated Protein Kinases