AsianScientist (Apr. 16, 2015) – Researchers have solved the structure of the adiponectin receptors, paving the way for the development of drugs which might prolong life and prevent diabetes. Their results have been published in Nature.
Adiponectin, a hormone secreted by fat cells, is known to be involved in the regulation of glucose and fatty acid oxidation. Its levels are reduced in patients with both type 1 and type 2 diabetes, and giving the hormone to mice has been reported to improve glucose intolerance. In addition, administration of a recently discovered adiponectin receptor agonist, AdipoRon, to genetically obese mice led to improved glucose intolerance and longer lifespans.
Since adiponectin binds to two receptors, AdipoR1 and AdipoR2, researchers have sought to understanding how this binding takes place in order to design drugs targeting these receptors. Adiponectin receptors are evolutionarily conserved in many living beings, including mammals, plants and yeasts, so it seemed clear that they should play an important biological role.
Using the microfocus beamline at the SPring-8 synchrotron facility, a team of researchers led by Professors Shigeyuki Yokoyama of RIKEN and Takashi Kadowaki and Toshimasa Yamauchi of the University of Tokyo obtained crystallographic images of the two receptors at resolutions of just 2.9 and 2.4 angstroms, and came up with a surprising finding.
The structure of the receptors was found to be a completely new type that is unlike G protein-coupled receptors, the most common type of receptor targeted by drug therapies. Intriguingly, the receptors were found to incorporate a zinc ion held in place by three histidine amino acid residues.
They also discovered that the receptors have large internal cavities, whose function is unknown, though Yokoyama speculates that they might be used as the entrance and exits for the substrates and products of the receptors’ activities.
“Analyzing the structure of these two receptors provided us with a number of interesting surprises,” Yokoyama said.
“We believe that this new information on the structure of the adiponectin receptors will help us understand new relationships between the structure and functions of these important receptors and hopefully will contribute to the development of new adiponectin receptor agonists that can be used for the treatment of obesity-related diseases such as type 2 diabetes. The discovery of the presence of a zinc ion is also fascinating, though more work will be required to understand its significance,” according to Yokoyama.
The article can be found at: Tanabe et al. (2015) Crystal structures of the human adiponectin receptors.
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Source: RIKEN; Photo: Tony Alter/Flickr/CC.
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