Scientists have identified the drug binding site in an enzyme that plays a key role in regulating glucose, fat and cholesterol metabolism, called AMP-activated protein kinase (AMPK).
The research, led by the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute), will allow scientists to begin designing drugs that activate AMPK to treat metabolic disorders such as obesity and type 2 diabetes.
The NIMR team worked with colleagues from the Medical Research Council's Clinical Sciences Centre at Imperial College and AstraZeneca in Sweden.
Matthew Sanders of NIMR explained: "AMPK is important for maintaining a constant level of energy (in the form of a molecule called ATP) within the body.
"It achieves this by stopping cells from making and storing fat and glucose, which use up energy. It also allows cells to burn off fat and glucose, which produces energy and helps restore the energy levels within the body.
"This makes AMPK an attractive drug target for treating metabolic disorders."
AMPK is made up of three subunits - called alpha, beta and gamma. It is activated when ATP levels in a cell decrease. Dr Steve Gamblin's group at NIMR previously showed that two binding sites in the gamma subunit are used by regulators of AMPK. And in 2006, Abbott Laboratories developed a potential drug that activates AMPK, which showed promise in treating aspects of the metabolic syndrome - a cluster of metabolic symptoms such as obesity that predispose people to heart disease and diabetes. However, despite a major effort since then to work out precisely how the drug activates AMPK, its specific binding site remained elusive.
In the current study, the researchers identified another molecule, more potent than the one made in 2006, that binds to and activates AMPK. They also used X-ray crystallography, which exposes crystals of the enzyme to X-rays, to determine the 3D structure of the whole AMPK complex when it was bound to each of the potential drugs.
This showed that there is a single site for drug binding at the interface between the alpha and beta subunits - a different site to those on the gamma subunit used by the enzyme's usual regulators.
Dr Sanders said: "This is the first time that anyone has been able to visualise the AMPK drug binding site and it will allow scientists to design drugs that 'fit' this site.
"The ability to visualise a drug binding site on any drug target is an enormous step forward for the scientific field and pharmaceutical industries."
The paper, Structural basis of AMPK regulation by small molecule activators, is published in Nature Communications.
