Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative disease and insulin resistance. The enzymes in question, which play a critical role in nerve cell (neuron) survival, are among the most prized targets for drugs to treat brain disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).
The study was published online ahead of print on November 8, 2012, by the journal Structure.
The new study reveals the structure of a class of enzymes called c-jun-N-terminal kinases (JNK) when bound to three peptides from different protein families; JNK is an important contributor to stress-induced apoptosis (cell death), and several studies in animal models have shown that JNK inhibition protects against neurodegeneration.
"Our findings have long-range implications for drug discovery," said TSRI Professor Philip LoGrasso, who, along with TSRI Associate Professor Kendall Nettles, led the study. "Knowing the structure of JNK bound to these proteins will allow us to make novel substrate competitive inhibitors for this enzyme with even greater specificity and hopefully less toxicity."
The scientists used what they called structure class analysis, looking at groups of structures, which revealed subtle differences not apparent looking at them individually.
"From a structural point of view, these different proteins appear to be very similar, but the biochemistry shows that the results of their binding to JNK were very different," he said.
LoGrasso and his colleagues were responsible for creating and solving the crystal structures of the three peptides (JIP1, SAB, and ATF-2) with JNK3 using a technique called x-ray crystallography, while Nettles handled much of the data analysis.
All three peptides have important effects, LoGrasso said, inducing two distinct inhibitory mechanisms—one where the peptide caused the activation loop to bind directly in the ATP pocket, and another with allosteric control (that is, using a location on the protein other than the active site). Because JNK signaling needs to be tightly controlled, even small changes in it can alter a cell's fate.
"Solving the crystal structures of these three bound peptides gives us a clearer idea of how we can block each of these mechanisms related to cell death and survival," LoGrasso said. "You have to know their structure to know how to deal with them."
Scripps Research Institute: http://www.scripps.edu
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Apeel Sciences hopes its products, which use natural methods to fend off pests and oxidization, can markedly reduce the amount of produce wasted because of spoilage.
Francis Halzen’s amazing experiment heralds the beginning of a new era in astronomy
First direct detection of dark matter, thought to make up most of the matter in the universe, would be a historic breakthrough
Geologists, climate scientists, ecologists and a lawyer gather in Berlin for talks on whether to rename age of human lifeHumanitys terrifying impact on Earth justifies new Anthropocene epoch
This month in Italy, three judges have a chance to undo the Kafkaesque nightmare that has ensnared some of the country’s top scientists for almost five years. So far it looks doubtful they will. In 2012, seven scientists and engineers were convicted of manslaughter for things they said and did not say in the days
Turkey's eternal fires have remained burning for thousands of years but now the source of the methane that fuels them has been found
Lockheed Martin Corp said on Wednesday it had made a technological breakthrough in developing a power source based on nuclear fusion, and the first reactors, small enough to fit on the back of a truck, could be ready for use in a decade.
But the hotspot predates the use of hydraulic fracking in the region, putting renewed attention on how older forms of natural gas production contribute to global climate change
A complicated technique used on LHC data for the first time has revealed two new particles, one of which has a combination of properties never seen before
Traditional method of insect harvesting is revived as cochineal insects are once-again valued for their brilliant red pigment