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MIT chemists have determined the molecular structure of a protein found in the SARS-CoV-2 virus. This protein, called envelope protein E, forms a selective channel for cations and plays a key role in the virus’s ability to replicate and stimulate the host cell’s inflammatory response.
If researchers could devise ways to block this channel, they might be able to reduce the pathogenicity of the virus and interfere with viral replication, says Mei Hong, a chemistry professor at MIT. In this study, the researchers investigated the binding sites of two channel-blocking drugs, but these drugs only bind weakly, so they would not be effective inhibitors of the E protein.
“Our findings could be useful for medicinal chemists to design alternative small molecules that target this channel with high affinity,” says Hong, who is the senior author of the new study.
MIT graduate student Venkata Mandala is the lead author of the article, which appears in Structural and molecular biology of nature. Other authors include MIT postdoc Matthew McKay, MIT graduate students Alexander Shcherbakov and Aurelio Dregni, and Antonios Kolocouris, professor of pharmaceutical chemistry at the University of Athens.
Structural challenges
Hong’s lab specializes in studying the structures of proteins that are embedded in cell membranes, which are often difficult to analyze due to lipid membrane disturbance. Using nuclear magnetic resonance (NMR) spectroscopy, she has previously developed several techniques that allow her to obtain atomically accurate structural information about these membrane-embedded proteins.
When the SARS-CoV-2 outbreak began earlier this year, Hong and his students decided to focus their efforts on one of the new coronavirus proteins. She focused on protein E in part because it’s similar to a flu protein called proton channel M2, which she has studied previously. Both viral proteins are made up of bundles of different helical proteins.
“We determined the structure of influenza B M2 after about 1.5 years of hard work, which taught us how to clone, express and purify a viral membrane protein from scratch and which NMR experimental strategies to adopt to solve the structure of a homo. -oligomeric helical beam, “Hong says. “That experience proved to be the perfect training ground for studying SARS-CoV-2 E.”
The researchers were able to clone and purify protein E in two and a half months. To determine its structure, the researchers incorporated it into a lipid bilayer, similar to a cell membrane, and then analyzed it with NMR, which uses the magnetic properties of atomic nuclei to reveal the structures of the molecules containing those nuclei. They measured NMR spectra for two months, continuously, on the highest-field NMR instrument at MIT, a 900 megahertz spectrometer, as well as on 800 and 600 megahertz spectrometers.
Hong and his colleagues found that the part of protein E embedded in the lipid bilayer, known as the transmembrane domain, assembles into a bundle of five helices. The propellers remain largely immobile within this beam, creating a narrow channel that is much narrower than the M2 channel of the flu.
The researchers also identified several amino acids at one end of the channel that can attract positively charged ions such as calcium into the channel. They believe the structure they report in this paper is the closed state of the canal and now hope to determine the structure of the open state, which should shed some light on how the canal opens and closes.
Fundamental research
The researchers also found that two drugs – amantadine, used to treat flu, and hexamethylene amiloride, used to treat hypertension – can block the entry of the E channel. However, these drugs only bind weakly. protein E. If more potent inhibitors could be developed, they could be potential drug candidates for the treatment of Covid-19, Hong says.
The study shows that basic scientific research can make an important contribution to solving medical problems, he adds.
“Even when the pandemic is over, it is important for our society to recognize and remember that fundamental scientific research on viral proteins or bacterial proteins must continue vigorously so that pandemics can be prevented,” says Hong. “The human cost and the economic cost of not doing so are just too high.”
The research was funded by the National Institutes of Health and the MIT School of Science Sloan Fund.
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