Hypertension, epilepsy and overactive bladder may be linked by electrical activity in a protein, and engineers at three universities are studying potential drug targets.
The seemingly unrelated conditions of hypertension, epilepsy and overactive bladder may be linked by electrical activity in a protein long studied by a biomedical engineer at Washington University in St. Louis. After new technology recently revealed the structure of the protein, this WashU lab will collaborate with two others to take an unprecedented look into its molecular mechanisms potentially leading to the development of new drugs for these and other conditions.
Jianmin Cui, professor of biomedical engineering in the School of Engineering & Applied Science, has received a four-year, $2.9 million grant from the National Institutes of Health to study the BK (big potassium) channel proteins in collaboration with labs from the University of Missouri-Columbia and the University of Massachusetts. The labs will each play a role in identifying new compounds that could go into the drug development pipeline.
Cells have ion channels across the cell membrane, which are pathways that conduct electrical currents into or out of the cell and open in response to physical signals, such as voltage, or chemical signals, such as calcium ions. But these channels typically allow only one type of ion to pass through, for example, the BK channel only allows potassium to pass through.
Recently, another lab used a new, Nobel-Prize-winning method called cryo-electron microscopy that allowed them to see the structure of the BK channel, which has given Cui's lab a fresh look at the channel's mechanisms. While researchers already knew the channel has three different domains — the voltage-sensing domain, the cytosolic domain and the pore domain— they do not know how sensors in other domains open the gate in the pore domain. Cui's lab seeks to find that pathway.
"In BK channel, the question is how would calcium binding in the cytosolic domain open the pore in the transmembrane pore domain," Cui said. "We have the structural information, but the structure itself cannot answer the question of how the two domains will interact to propagate and transfer the movements in calcium binding that causes the cytosolic domain to open."
To answer the question, a lab at the University of Missouri-Columbia will identify chemical compounds that would bind and modify the channel protein to probe the parts of the channel protein that move upon calcium binding. They will pick out those compounds from a library of about a quarter of a million chemicals with known structures stored in computers. They will compare the structures of these chemicals one by one to potential sites in the channel protein using computers in an operation called docking, which may identify a handful of chemical compounds that might bind to the channel protein. Then they will apply the real compound of these hits from the in silico (in computer) screening to treat BK channels in cells and test if they modify channel function.
At the University of Massachusetts, a team will simulate the motion of part of the protein to see if those motions are important in propagating the calcium-binding-induced movements to the pore.
Finally, Cui's lab will study the function of the channels by recording ionic currents flowing through these channels. These recordings, in combination with mutating the channel protein and some molecular modeling, will allow the lab to determine if the changes they see in the experiments and in simulation are factors for propagation.
"We want to know where the structure changes, how does it change and what makes it change," Cui said. "These understandings, along with the identification of compounds and their binding sites, could lead to the development of drugs for treating BK channel-related diseases."
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