New drugs could be inspired by understanding how P2X7 protein receptor works
For the first time, researchers have observed at the molecular level how a protein associated with numerous health problems works.
An illustration shows how the P2X7 protein receptor opens and closes, allowing charged particles to enter a cell and trigger cellular changes. OHSU resarchers used cryoelectron microscopy to obtain the protein's 3D structure for the first time. P2X7 is associated with many diseases, including inflammation, coronary artery disease, cancer and multiple sclerosis.
Credit: Oregon Health & Science University
The discovery - which could one day inspire new drugs to treat inflammation, coronary artery disease, cancer, multiple sclerosis and more - was published today in the journal Cell.
Oregon Health & Science University research assistant Alanna McCarthy, B.S., and OHSU researcher Steven Mansoor, M.D., Ph.D., used cryoelectron microscopy to obtain the 3D structure of a protein receptor and observe its inner workings. The protein receptor they studied is a cellular membrane protein that allows electrically charged sodium and calcium particles to enter and trigger changes in a cell.
They specifically studied the P2X7 receptor, a subtype of the ligand-gated ion channel P2X family that has been associated with inflammation, plaque buildup in arteries, cancer metastasis, neurological conditions and more.
P2X7 is unusual because once activated, its channel remains open indefinitely, continually allowing charged particles to enter a cell and trigger the signaling pathways of inflammation, ultimately leading to cell death. Such signaling behavior could contribute to the long list of ailments that are associated with the receptor.
Unlike previous efforts to image the P2X7 receptor, the team's cryo-EM imaging approach allowed them to capture the protein receptor in its entirety.
This enabled them to visualize the parts of the receptor that sit inside the cell. As a result, they were able to directly observe how these parts are modified with fatty acid molecules called palmitoyl groups. When Mansoor and his colleagues removed these groups, they found the receptor no longer stayed open indefinitely, shutting down its ability to trigger signaling. They also unexpectedly discovered a guanosine nucleotide was bound to P2X7 inside the cell.
"Researchers have known ligand-gated ion channels are modified by palmitoyl groups, but we had never directly observed it until now," said Mansoor, an assistant professor of medicine (cardiovascular) in the OHSU School of Medicine and Knight Cardiovascular Institute. "Our finding could be used as a model of how palmitoylation modifies other ion channels."
Mansoor and his team will further explore the roles that palmitoyl groups and the guanosine nucleotide play in P2X7 intra-cellular signaling, their potential impact on human health, and how they could be targeted to treat health conditions associated with the receptor.
This research was supported by the National Heart, Lung and Blood Institute (grant K99HL138129). The team used microscopes at the Pacific Northwest Center for Cryo-EM, which OHSU and Pacific Northwest National Laboratory established in 2018 with support of the National Institutes of Health, and conducted research in the OHSU Vollum Institute lab of Eric Gouaux, Ph.D., who is supported by the Howard Hughes Medical Institute.
REFERENCE: Alanna E. McCarthy, Craig Yoshioka, Steven E. Mansoor, Full-length P2X7 structures reveal how palmitoylation prevents channel desensitization, Cell, 11 a.m. ET Oct. 3, 2019, DOI: 10.1016/j.cell.2019.09.017, https:/
Related OHSU News Stories:
* 9/14/16 OHSU News Hub story, "Study in Nature Reveals News Molecular Insight," https:/
* 5/15/18 OHSU News Hub story, "OHSU one of three centers selected to study cells at atomic level," https:/
* Steven Mansoor, M.D., Ph.D., https:/
* OHSU Foundation Onward Magazine, July 1, 2017, "Up-and-comers: Steven Mansoor," https:/
Franny White | EurekAlert!
New deep-water coral discovered
22.10.2019 | Smithsonian Tropical Research Institute
DNA-reeling bacteria yield new insight on how superbugs acquire drug-resistance
22.10.2019 | Indiana University
Researchers have succeeded in creating an efficient quantum-mechanical light-matter interface using a microscopic cavity. Within this cavity, a single photon is emitted and absorbed up to 10 times by an artificial atom. This opens up new prospects for quantum technology, report physicists at the University of Basel and Ruhr-University Bochum in the journal Nature.
Quantum physics describes photons as light particles. Achieving an interaction between a single photon and a single atom is a huge challenge due to the tiny...
A very special kind of light is emitted by tungsten diselenide layers. The reason for this has been unclear. Now an explanation has been found at TU Wien (Vienna)
It is an exotic phenomenon that nobody was able to explain for years: when energy is supplied to a thin layer of the material tungsten diselenide, it begins to...
Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich have explored the initial consequences of the interaction of light with molecules on the surface of nanoscopic aerosols.
The nanocosmos is constantly in motion. All natural processes are ultimately determined by the interplay between radiation and matter. Light strikes particles...
Particles that are mere nanometers in size are at the forefront of scientific research today. They come in many different shapes: rods, spheres, cubes, vesicles, S-shaped worms and even donut-like rings. What makes them worthy of scientific study is that, being so tiny, they exhibit quantum mechanical properties not possible with larger objects.
Researchers at the Center for Nanoscale Materials (CNM), a U.S. Department of Energy (DOE) Office of Science User Facility located at DOE's Argonne National...
A new research project at the TH Mittelhessen focusses on the development of a novel light weight design concept for leisure boats and yachts. Professor Stephan Marzi from the THM Institute of Mechanics and Materials collaborates with Krake Catamarane, which is a shipyard located in Apolda, Thuringia.
The project is set up in an international cooperation with Professor Anders Biel from Karlstad University in Sweden and the Swedish company Lamera from...
02.10.2019 | Event News
02.10.2019 | Event News
19.09.2019 | Event News
22.10.2019 | Life Sciences
22.10.2019 | Life Sciences
22.10.2019 | Power and Electrical Engineering