The structure of a key part of the human obesity receptor has been defined, and could help in the provision of treatments resulting from obesity and anorexia.
Using X-ray crystallography, researchers from the University of Sheffield solved the challenging crystal structure of the leptin-binding domain of the obesity receptor (ObR). They crystallised the Fab fragment of leptin-blocking monoclonal antibody (9F8) both in an uncomplexed state and bound to the leptin-binding domain (LBD) of ObR.
They discovered that 9F8 blocks leptin binding through a small overlap in binding site, and that leptin binding is likely to involve an induced fit mechanism.
“Using X-ray crystallography we have solved the structure of the leptin-binding domain of the receptor bound to a potential therapeutic antibody that blocks leptin binding. This is the first crystal structure for any part of this important receptor,” said Professor Pete Artymiuk.
“Because we now know the precise atomic structure of the receptor we can begin to design drug molecules that can alter disease activity.”
The researchers believe that knowing the structure will greatly enhance their ability to generate drugs which can both block and stimulate the receptor. This could have life-changing effects for people suffering from complications of obesity and malnutrition.
Leptin is produced by fat and excess leptin predisposed overweight people to conditions like multiple sclerosis, cancer and heart disease, while a leptin deficiency – occurring in malnutrition – results in infertility and immunodeficiency.
“This pioneering research gives us the potential to generate new drugs that could treat conditions and diseases associated with obesity such as multiple sclerosis, diabetes and cardiovascular disease,” said Richard Ross, Professor of Endocrinology.
“Modulating the actions of the obesity receptor provides a novel approach to the treatment of conditions associated with both obesity and anorexia and has the potential to make a massive difference to millions of people whose quality of life is hindered by obesity or malnutrition.”