2YZA

Crystal structure of kinase domain of Human 5'-AMP-activated protein kinase alpha-2 subunit mutant (T172D)

Summary for 2YZA

• Entry DOI: 10.2210/pdb2yza/pdb
• Related: 2H6D
• Descriptor: 5'-AMP-activated protein kinase catalytic subunit alpha-2 (2 entities in total)
• Functional Keywords: signaling protein, serine/threonine protein kinase, phosphorylation, atp-binding, nucleotide-binding, cholesterol biosynthesis, fatty acid biosynthesis, lipid synthesis, glucose metabolism, magnesium, metal-binding, serine/threonine-protein kinase, steroid biosynthesis, transferase, structural genomics, nppsfa, national project on protein structural and functional analyses, riken structural genomics/proteomics initiative, rsgi
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (By similarity): P54646
• Total number of polymer chains: 1
• Total formula weight: 31571.73

Authors

Saijo, S.,Takagi, T.,Yoshikawa, S.,Kishishita, S.,Shirouzu, M.,Yokoyama, S.,RIKEN Structural Genomics/Proteomics Initiative (RSGI) (deposition date: 2007-05-04, release date: 2008-05-06, Last modification date: 2023-10-25)

Primary citation

Handa, N.,Takagi, T.,Saijo, S.,Kishishita, S.,Takaya, D.,Toyama, M.,Terada, T.,Shirouzu, M.,Suzuki, A.,Lee, S.,Yamauchi, T.,Okada-Iwabu, M.,Iwabu, M.,Kadowaki, T.,Minokoshi, Y.,Yokoyama, S.
Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha 2 subunit kinase domain
Acta Crystallogr.,Sect.D, 67:480-487, 2011

PubMed 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.

PubMed: 21543851
DOI: 10.1107/S0907444911010201

Experimental method

X-RAY DIFFRACTION (3.02 Å)