Author
Listed:
- Bing Xiao
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill)
- Matthew J. Sanders
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill)
- David Carmena
(MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College)
- Nicola J. Bright
(MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College)
- Lesley F. Haire
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill)
- Elizabeth Underwood
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill)
- Bhakti R. Patel
(MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College)
- Richard B. Heath
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill
Present address: Northern Institute for Cancer Research, Newcastle University, Paul O’Gorman Building Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK)
- Philip A. Walker
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill)
- Stefan Hallen
(Bioscience, CVMD Innovative Medicine Unit, AstraZeneca R&D, Pepparedsleden 1)
- Fabrizio Giordanetto
(Medicinal Chemistry, CVMD Innovative Medicine Unit, AstraZeneca R&D, Pepparedsleden 1
Present address: Medicinal Chemistry, Taros Chemicals GmbH & Co. KG, Emil-Figge-Str. 76a, 44227 Dortmund, Germany)
- Stephen R. Martin
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill)
- David Carling
(MRC Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College)
- Steven J. Gamblin
(MRC National Institute for Medical Research, The Ridgeway, Mill Hill)
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.
Suggested Citation
Bing Xiao & Matthew J. Sanders & David Carmena & Nicola J. Bright & Lesley F. Haire & Elizabeth Underwood & Bhakti R. Patel & Richard B. Heath & Philip A. Walker & Stefan Hallen & Fabrizio Giordanetto, 2013.
"Structural basis of AMPK regulation by small molecule activators,"
Nature Communications, Nature, vol. 4(1), pages 1-10, December.
Handle:
RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms4017
DOI: 10.1038/ncomms4017
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