In many pharmaceutical company and university laboratories, scientists are looking closely at kinase complexes because the enzymes play key roles in essential cell functions.
By taking unusual steps to examine a kinase complex, researchers at Brown University and the National Institutes of Health have found a sought-after prize: an unprecedentedly detailed description of its structure complete with a rare location on its structure that could be a target for new therapeutic drugs.
"Disregulation always leads to disease," said Wolfgang Peti, associate professor of medicine and chemistry at Brown University and senior author of a paper published online Nov. 6 in Nature Chemical Biology. "To make better drugs, what we want to do is look for individual things that are different between different complexes. The problem is we didn't know where those non-common spots are. We didn't have the structures that tell us the story. We were the first to get one of those structures."
The complex that Peti, Brown colleague Rebecca Page, and their team has now characterized is hardly a household name: p38alpha:HePTP. It does however, matter in millions of households around the world. It is a member of the MAP kinase family, enzymes that regulate cell functions such as growth and inflammation. Diseases that correlate with disruptions to MAP kinase signaling include Alzheimer's disease, rheumatoid arthritis, and cancer.
To determine the structure, the group took the rare step of combining techniques including nuclear magnetic resonance spectroscopy and small-angle X-ray scattering, using the National Synchrotron Light Source at Brookhaven National Laboratory on Long Island. The result was the clearest picture yet of a MAP kinase complex, which turns out to measure a mere 108 Angstroms (tenths of billionths of a meter) long by 30 Angstroms wide. The resolution of their resulting model is on the scale of individual atoms.
To elucidate their model, they probed the complex to discover areas where p38alpha binds to different HePTP-derived peptides. They found a specific area called "KIS" that is responsible for how the p38alpha:HePTP complex forms in its unique way.
"That really showed there are these areas outside the common sites that are likely unique between different complexes," Peti said.
The next step is to learn more about KIS and the role it could ultimately play in disregulation and disease. In their paper, the authors expressed optimism that their newfound knowledge will have clinical relevance: "These results provide novel insights into the molecular interactions that regulate the strength and duration of MAP kinase signaling and, in turn, provide novel avenues for therapeutic interventions of MAP kinase-related diseases."
In addition to Peti and Page, other Brown authors include lead author Dana Francis and co-author Dorothy Koveal. Authors from the National Institute of Diabetes and Digestive and Kidney Diseases were Bartosz Rozycki and Gerhard Hummer.
The American Cancer Society funded the research.
David Orenstein | EurekAlert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
21.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
21.08.2017 | Materials Sciences
21.08.2017 | Health and Medicine
21.08.2017 | Materials Sciences