The genome of the SARS-CoV-2 virus encodes 29 proteins, one of which is an ion channel called E. This channel, which transports protons and calcium ions, induces infected cells to launch an inflammatory response that damages tissues and contributes to the symptoms of COVID-19.
MIT chemists have now discovered the structure of the “open” state of this channel, which allows ions to flow through. This structure, combined with the “closed” state structure that was reported by the same lab in 2020, could help scientists figure out what triggers the channel to open and close. These structures could also guide researchers in developing antiviral drugs that block the channel and help prevent inflammation.
“The E channel is an antiviral drug target. If you can stop the channel from sending calcium into the cytoplasm, then you have a way to reduce the cytotoxic effects of the virus,” says Mei Hong, an MIT professor of chemistry and the senior author of the study.
MIT postdoc Joao Medeiros-Silva is the lead author of the study, which appears in Science Advances. MIT postdocs Aurelio Dregni and Pu Duan and graduate student Noah Somberg are also authors of the paper.
Once they established the closed structure, the researchers set out to determine the structure of the open state of the channel. To induce the channel to take the open conformation, the researchers exposed it to a more acidic environment, along with higher calcium ion levels. They found that under these conditions, the top opening of the channel (the part that would extend into the ERGIC) became wider and coated with water molecules. That coating of water makes the channel more inviting for ions to enter.
That pore opening also contains amino acids with hydrophilic side chains that dangle from the channel and help to attract positively charged ions.
The researchers also found that while the closed channel has a very narrow opening at the top and a broader opening at the bottom, the open state is the opposite: broader at the top and narrower at the bottom. The opening at the bottom also contains hydrophilic amino acids that help draw ions through a narrow “hydrophobic gate” in the middle of the channel, allowing the ions to eventually exit into the cytoplasm.
Near the hydrophobic gate, the researchers also discovered a tight “belt,” which consists of three copies of phenylalanine, an amino acid with an aromatic side chain. Depending on how these phenylalanines are arranged, the side chains can either extend into the channel to block it or swing open to allow ions to pass through.
