First structure of key COVID enzyme at human body temperature: Subtle structural changes in virus’s ‘main protease’ over a range of temperatures may point to new targets for antiviral drugs

Scientists studying a COVID-19 coronavirus enzyme at temperatures ranging from frosty to human-body warm discovered subtle structural shifts that offer clues about how the enzyme works. The findings, published in IUCrJ, the journal of the International Union of Crystallography, may inspire the design of new drugs to counteract COVID-19 — and possibly help head off future coronavirus pandemics.

“No previous study has looked at this important coronavirus enzyme at physiological (or body) temperature,” said Daniel Keedy, a structural biologist at the City University of New York (CUNY), who conducted the study in collaboration with scientists at the U.S. Department of Energy’s Brookhaven National Laboratory.

Most structures to date come from frozen samples — far from the temperatures at which the molecules operate within living cells. “If you are working at physiological temperature, you should get a more realistic picture of what’s happening during an actual infection, because that’s where biology happens,” Keedy said.

In addition, he added, the team used temperature as a tool. “By turning that knob and seeing how the protein reacts, we can learn about its mechanics — how it physically works.

Deciphering Mpro’s structure

The protein in question is the main protease (Mpro) of SARS-CoV-2, the virus that causes COVID-19. Like all proteases, it’s an enzyme that cuts other proteins. In many viral infections, including COVID-19, infected cells initially produce a virus’s functional proteins as one single connected protein chain. Proteases cut the pieces apart so the individual proteins can make and assemble themselves into new copies of the virus. Finding a drug to disable Mpro could put the brakes on COVID-19.

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