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Structural basis of AMPK regulation by small molecule activators

DOI: 10.1038/ncomms4017 DOI Help
PMID: 24352254 PMID Help

Authors: Bing Xiao (National Institute for Medical Research, Medical Research Council) , Matthew Sanders (NIMR) , David Carmena (MRC National Institute for Medical Research) , Nicola J. Bright (MRC National Institute for Medical Research) , Lesley F. Haire (National Institute for Medical Research, Medical Research Council) , Elizabeth Underwood (NIMR) , Bhakti R. Patel (MRC National Institute for Medical Research) , Richard Heath (MRC, National Institute for Medical Research) , Phil Walker (MRC National Institute for Medical Research) , Stefan Hallen (Bioscience, CVMD Innovative Medicine Unit, AstraZeneca R&D) , Fabrizio Giordanetto (Medicinal Chemistry, CVMD Innovative Medicine Unit, AstraZeneca R&D) , Stephen R. Martin (National Institute for Medical Research, Medical Research Council) , David Carling (MRC National Institute for Medical Research) , Steven Gamblin (National Institute for Medical Research, Medical Research Council)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 4

State: Published (Approved)
Published: December 2013
Diamond Proposal Number(s): 7707

Open Access Open Access

Abstract: AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders.

Journal Keywords: Adenosine; Allosteric; Binding; Carbohydrates; Circular; Crystallography; X-Ray; Gene; Enzymologic; HEK293; Humans; Interferometry; Phosphorylation; Protein; Tertiary; Recombinant; Threonine

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

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