The findings could guide design of future therapies
Scientists thought they basically knew how the most common drugs used to treat type 2 diabetes worked, but a new study from the Florida campus of The Scripps Research Institute (TSRI) reveals unexpected new aspects of the process. These findings could eventually lead to more potent anti-diabetic drugs with fewer serious side effects.
Douglas Kojetin, Ph.D., is an associate professor at the Scripps Research Institute, Florida campus.
Credit: Photo courtesy of the Scripps Research Institute
The study was published in the April 7, 2014 issue of the journal Nature Communications.
The most common type 2 diabetes treatments are known as insulin-sensitizing drugs, which improve how the body responds to glucose or sugar. These drugs mimic naturally occurring compounds that bind to a specific intracellular receptor (peroxisome proliferator-activated receptor-γ or PPARG), altering its activity.
While these drugs were widely thought to bind to a single site on the receptor, the new study shows they also bind to an alternative site, leading to unique changes in receptor shape, which affects interaction with co-regulating protein partners and gene expression.
Douglas Kojetin, an associate professor at TSRI who led the study, called the discovery serendipitous—and revealing.
"It turns out that binding to PPARG is far more complex than anyone previously understood," he said. "You don't have to displace the naturally occurring ligand [binding partner] with a synthetically designed drug to regulate the receptor because you have this alternative site."
Kojetin and his colleagues made the alternative binding site discovery using a far simpler mapping technique than had previously been applied to determine the receptor's structure.
"We used a technique that yields easy-to-interpret results, one that you wouldn't normally use to look at how drugs bind a receptor," said Research Associate Travis Hughes, the first author of the study and a member of Kojetin's lab. "Instead of finding one site, we realized we had two and wanted to know what the second one was doing."
The scientists note that while they don't yet know the full effect of the alternate binding site's function, it might provide a clue to insulin-sensitizing drugs' adverse effects, which include risk of bone loss and congestive heart failure.
"The question going forward is 'Does this alternative site contribute to side effects, beneficial effects or both?'" said Kojetin. "Knowledge of this alternate binding site may help produce a new generation of anti-diabetic drugs."
In addition to Kojetin and Hughes, authors of the study, "An Alternate Binding Site for PPARγ Ligands," include Pankaj Kumar Giri, Ian Mitchelle S. de Vera, David P. Marciano, Dana S. Kuruvilla, Youseung Shin, Anne-Laure Blayo, Theodore M. Kamenecka and Patrick R. Griffin of TSRI; and Thomas P. Burris of St. Louis University.
The study was supported by the state of Florida, the James and Esther King Biomedical Research Program, the Florida Department of Health (grant number 1KN-09) and the National Institutes of Health (grant numbers DK101871 and DK097890).
Eric Sauter | EurekAlert!
New Technique Maps Elusive Chemical Markers on Proteins
03.07.2015 | Salk Institute for Biological Studies
New approach to targeted cancer therapy
03.07.2015 | CECAD - Cluster of Excellence at the University of Cologne
Wind turbines could be installed under some of the biggest bridges on the road network to produce electricity. So it is confirmed by calculations carried out by a European researchers team, that have taken a viaduct in the Canary Islands as a reference. This concept could be applied in heavily built-up territories or natural areas with new constructions limitations.
The Juncal Viaduct, in Gran Canaria, has served as a reference for Spanish and British researchers to verify that the wind blowing between the pillars on this...
New technique combines electron microscopy and synchrotron X-rays to track chemical reactions under real operating conditions
A new technique pioneered at the U.S. Department of Energy's Brookhaven National Laboratory reveals atomic-scale changes during catalytic reactions in real...
Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and a half billion years ago.
Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and...
A team of scientists including PhD student Friedrich Schuler from the Laboratory of MEMS Applications at the Department of Microsystems Engineering (IMTEK) of...
The three-year clinical trial results of the retinal implant popularly known as the "bionic eye," have proven the long-term efficacy, safety and reliability of...
25.06.2015 | Event News
16.06.2015 | Event News
11.06.2015 | Event News
03.07.2015 | Press release
03.07.2015 | Agricultural and Forestry Science
03.07.2015 | Health and Medicine