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Structural basis of AMPK regulation by small molecule activators
Bing Xiao1, Matthew J Sanders1, David Carmena2
11] MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK [2].
Nature Communications
|December 20, 2013
Summary
Researchers elucidated the structure of AMP-activated protein kinase (AMPK) bound to an activator. This finding provides a structural basis for activator binding and aids in designing new therapies for metabolic disorders.
Area of Science:
- Biochemistry
- Structural Biology
- Metabolic Regulation
Background:
- AMP-activated protein kinase (AMPK) regulates cellular energy balance.
- AMPK is a therapeutic target for metabolic diseases like type 2 diabetes and cancer.
- A structural basis for small molecule activator binding to AMPK was previously lacking.
Purpose of the Study:
- To present the crystal structure of human AMPK in complex with a small molecule activator.
- To understand the binding site and mechanism of AMPK activation.
- To provide a foundation for designing novel AMPK-targeting therapeutics.
Main Methods:
- X-ray crystallography
- Determination of the human AMPK-activator complex structure
Main Results:
- The crystal structure reveals a small molecule activator binding between the kinase domain and carbohydrate-binding module.
- This binding stabilizes the interaction between these two AMPK components.
- The activator-binding pocket suggests a role for an unidentified metabolite in AMPK regulation.
Conclusions:
- The determined structure provides the first structural basis for small molecule activator binding to AMPK.
- This structural insight facilitates the rational design of new AMPK activators.
- Potential applications include the development of treatments for metabolic disorders.
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