X-ray solution to obesity: Structural target revealed

An appetite for deconstruction

 

Researchers at the University of Sheffield, UK, have used X-ray crystallography to obtain a detailed structure of a key component of the human obesity receptor, the binding domain for the satiety hormone leptin.

The research opens up this essential factor in the regulation of body fat as a potential target for novel treatments for conditions such as obesity and anorexia nervosa. The researchers suggest that ultimately the work could have a life-changing impact for many people suffering from the complications of obesity or conversely malnutrition.

Leptin is known colloquially as an obesity hormone is closely tied to the basic physiological drive of ones's appetite for nutrition which ultimately ties its activity to many other aspects of physiology, such as the immune response and even fertility all of which are tempered by long-term nutrition levels. It is produced by fat cells and an excess predisposes a person to becoming overweight, given a sufficiently high-calorie diet and a lack of exercise. The molecule is a 16 kilodalton protein and fundamentally regulate energy intake and energy expenditure by controlling appetite and metabolism. It is is often described as among the most critical hormones derived from adipose tissue. The same hormone in excess is also a risk factor for debilitating and potentially fatal conditions such as multiple sclerosis, cancer and heart disease. Conversely, a leptin deficiency is associated with malnutrition leading to immunodeficiency and fertility problems.

Overweight drug targets

Drugs that can stimulate or inhibit the obesity receptor (ObR), agonists or antagonists, respectively, could be used to modulate the effects of an excess or deficiency in this hormone. They might this be used to avoid some of the morbid complications of obesity and malnutrition. Endocrinologist Richard Ross explains that, "This pioneering research gives us the potential to generate new drugs that [offer] 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 and health is hindered by obesity or malnutrition."

Team member Pete Artymiuk explains that the researchers have obtained a crystal structure of the leptin binding domain of the receptor within which was bound a potential therapeutic antibody (9F8) that inhibits leptin binding. This is the first crystal structure for any part of this important receptor, Artymiuk says. "Because we now know the precise atomic structure of the receptor we can begin to design drug molecules that can alter its activity."

"The structures of 9F8 Fab in both its uncomplexed and receptor-bound forms give valuable insight into its mechanism of antigen recognition," the team explains in a recent issue of the journal Structure. "Electrostatic interactions, shape complementarity and conformational rearrangement all play an important role in antigen binding." The researchers add that the model constructed from the X-ray data predicts that the primary site of leptin binding within the C-terminal subdomain of LBD is probably the J-K loop. "The crystal structure of LBD revealed [this] to be highly flexible," the team adds. "This provides strong evidence that leptin binding involves an induced fit mechanism.