With a combination of chemical labeling and mass spectrometry, a team of researchers from Oxford University and Case Western Reserve University's School of Medicine Center for Proteomics and Bioinformatics took the first high-resolution picture of the open state of a potassium ion channel.
The method, which uses a mass spectrometry-based structural imaging technology, has allowed the researchers to comparatively analyze gating mechanisms crucial to heart and nerve function, as well as achieve new insight into G-protein coupled receptors.
Sayan Gupta, an instructor at Case Western, says this new method could pave the way for a deeper understanding of how pharmaceutical drugs — many of which target GPCRs — can be made more effective. "This is the first time we are able to study the same protein, the same type of channel on the same source, both closed and open, under the same conditions — there are no other studies like this," Gupta says. "Now we are able to identify the regions that are actually functionally important, see how the function is affected and ... by using some assays, focus on those regions that we see will have a direct application for some drug interactions as well as the effect of some ligands which can be used by drugs to control the gating of this potassium channel."
The research team, led by Case Western's Mark Chance, has already published evidence for a recently developed potassium ion channel gating mechanism that holds some promise for the exploration of other membrane proteins and ion channels.
"We are planning on working on other types of potassium channels — this is just one type, there are several other potassium channels," Gupta says. "We are also focusing on integral membrane proteins, such as transporters, receptors, pores — all of which have been very difficult to study by other high-resolution techniques [like] lithography and NMR."
Gupta and his colleagues have also received a four-year, $1.1 million grant from the National Institute of Biomedical Imaging and Bioengineering to further refine methods of exploring GPCRs using improved mass spec and novel oxygen-18 based water labeling techniques.