Solving AMPK

The enzyme AMP-activated protein kinase (AMPK) has been shown to be central to regulating several metabolic systems such as glucose uptake, oxidation of fatty acids, and insulin sensitivity, but the crystal structure of the mammalian enzyme remained elusive.ﾠBing Xiao and others from the United Kingdom's National Institute for Medical Research used X-ray crystallography to map the structure of AMPK when bound to AMP and ATP, which the enzyme binds competitively, ¹ illuminating AMPK regulation.

"This is the first study to reveal the structural basis for AMP binding to mammalian AMPK," writes Anthony Means of the Duke University Medical Center on the Faculty of 1000 Web site. Means comments that Xiao's paper provides a hypothesis of how AMP affects AMPK activity. The enzyme consists of three protein subunits labeled α, β, and γ. This study suggests that when AMP binds to the γ subunit, the enzyme undergoes a conformational change that exposes an active site on the α subunit, which is the kinase unit. But since the enzyme used for this model is a truncated version that does not include the entire α unit, the exact mechanism of AMPK activity on regulating metabolic systems remains undetermined.

Since AMPK regulates insulin sensitivity and glucose metabolism, and is activated by metformin (one of the most commonly used treatments of type II diabetes), illuminating a detailed mechanism of AMPK activity could lead to new understanding of how this and other therapeutics treat obesity and diabetes.