This article has been reviewed according to ScienceX's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:
fact-checked
peer-reviewed publication
proofread
by Gerhard Samulat , European XFEL
close
The COVID-19 pandemic resulted in millions of deaths. Despite an unparalleled collaborative research effort that led to effective vaccines and therapies being produced in record-breaking time, a complete understanding of the structure and lifecycle of the coronavirus known as SARS-CoV-2 is still lacking.
Scientists used the biolabs and the SPB/SFX instrument at the European XFEL to study the main protease, or Mpro, of the virus to understand how it protects itself from oxidative damage. The results add key knowledge to our understanding of the workings of SARS-CoV-2 and the field of viral biology.
The paper is published in the journal Nature Communications.
Between January 2020 and March 2023, over six million people died as a result of the respiratory disease COVID-19, and several hundred million were infected. The disease is caused by SARS-CoV-2, a coronavirus.
"Coronaviruses are a group of RNA viruses that cause illnesses and diseases in mammals and birds," explains European XFEL scientist Richard Bean. "However, despite their significant relevance for global human health, there is still a lot to learn about the structure and function of coronaviruses in general and SARS-CoV-2 in particular."
In response to the outbreak of the pandemic, scientists and scientific organizations around the globe poured efforts into studying the structure, dynamics, and function of SARS-CoV-2 in search of vaccines and therapies. Due to its central role in the replication cycle of the virus, the main proteasean enzyme that liberates newly made pieces of the virus from one anothersoon emerged as a key antiviral drug target.
The main protease, or Mpro, is particularly attractive for drug development because it plays a central role in viral replication, and also because it is quite different from all human proteins. This allows therapies to specifically target the virus while minimizing side effects that might harm patients. Previous drug discovery programs targeting other viruses have succeeded using viral protease inhibitors, making a successful outcome in the case of SARS-CoV-2 more likely.
"While the height of the COVID-19 pandemic may have passed, there is still a lot of value in studying the SARS-CoV-2 virus," says Thomas Lane from the Center for Free-Electron Laser Science (CFEL) in Hamburg. "COVID continues to present a significant health threat worldwide. Given the persistence of this virus and the possible emergence of future pathogenic coronaviruses, it is imperative we develop a deeper understanding of Mpro and its role in viral function."
In a recent experiment at the SPB/SFX instrument at the European XFEL, Lane and colleagues used the intense X-ray beam to study Mpro. Several previous structural studies focusing on Mpro have highlighted a number of peculiarities.
"Firstly, the protein forms a 3D structure known as a dimer when it is found in high concentrations," explains European XFEL scientist Robin Schubert, who was involved in the experiment. "This structural habit seems to directly influence its activitybut we don't know precisely why this is important for the virus." Alongside key insights into the 3D structure, recent studies have also hinted at the importance of cellular oxygen levels for protease activity.
"It seems that even mild exposure to oxygen decreases Mpro's activity," explains Patrick Reinke, also from CFEL. Indeed, in the presence of sufficient oxygen, turnover ceases altogether. But this process is reversibleif the oxygen is removed, the enzyme reactivates itself, suggesting the system has evolved protective mechanisms to survive in an oxidative environment.
"Oxidative stress has been shown to regulate the function of other viruses, such as HIV," Reinke adds. "It has been suggested that structural changes in the protease let it escape oxidative damage in oxygen-rich environments. However, we're still unsure of how these protective mechanisms impact viral fitness."
To better understand how structural changes protect the protein from oxygen damage, the team used the European XFEL's powerful X-ray beam to reveal the structure of Mpro after it had been exposed to oxygen. They discovered a structural rearrangement of Mpro in which a bond forms between two cysteine residues: the active site cysteine C145 and a distal cysteine C117.
To accomplish this, the team produced large amounts of Mpro over the course of several months in the biolabs at European XFEL and turned it into microcrystals, some of which were grown in the presence of oxygen. Finally, the microcrystals were sent flying in front of the European XFEL beam at the SPB/SFX instrument using a liquid jet.
Such small crystals are impossible to study using traditional light sources because the amount of radiation needed to generate enough data from the crystals would destroy them. The X-rays pulses produced by the European XFEL, however, are so powerful and short that they can be used to capture an image of the protein crystal before it has time to disintegrate.
"Our results show that the active site cysteine, which conducts the enzyme's chemistry, can sneakily hide itself from oxidative damage," says Schubert. Typically, oxidation can irreversibly damage cysteines.
Upon oxidation, however, Mpro protects its most important cysteine by forming what is known as a "disulfide bond," which buries it in the core of the protein structure. Then, if moved back into a safe, low-oxygen environment, the disulfide bond can break, revealing the active cysteine, which resumes its original function.
"The experiments performed at the European XFEL reveal a picture of the protein in its hidden disulfide state, confirming it exists and uncovering how it works," says Schubert.
"Mpro exhibits an unusually rich set of oxidation modifications, and our experiment adds a key piece to that story," says Lane. The scientists are excited about what their data indicate and about their next steps. "Mpro is a linchpin of coronavirus biology and the premier target for anti-COVID-19 small-molecule therapeutics.
"The enzyme's function has been shown to be regulated via both dimerization and oxidation, and it's clear that these regulatory mechanisms are biophysically correlated. While our structures provide mechanistic insight into these properties of Mpro, we must now understand how regulation based on oxidative stress or protein concentration impact viral fitness. This will provide deeper insight into viral biology and hopefully open new opportunities to disrupt that biology with life-preserving medicines."
More information: Patrick Y. A. Reinke et al, SARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds, Nature Communications (2024). DOI: 10.1038/s41467-024-48109-3
Journal information: Nature Communications
Provided by European XFEL
Read the rest here:
- The Health Department website was attacked in the middle of the coronavirus pandemic - Vox.com [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Defining Coronavirus Symptoms: From Mild To Moderate To Severe : Goats and Soda - NPR [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- What Are the Symptoms of a Coronavirus Infection? - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Hotels Were Rolling Out Tools to Help Calm Travelers. Then Coronavirus Hit. - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- The Coronavirus, by the Numbers - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Opinion: Early Coronavirus Testing Failures Will Cost Lives - NPR [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus Cases Surge in U.S. and Europe - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Two Emergency Room Doctors Are in Critical Condition With Coronavirus - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus: Over 1000 Cases Now In U.S., And 'It's Going To Get Worse,' Fauci Says - NPR [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- China Spins Tale That the U.S. Army Started the Coronavirus Epidemic - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Everything to Know About the Coronavirus in the United States - The Cut [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus closed this school. The kids have special needs: 'You can't Netflix them all day.' - USA TODAY [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- How Long Can The Coronavirus Live On Surfaces? : Shots - Health News - NPR [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus Cost to Businesses and Workers: It Has All Gone to Hell - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- In the U.S., More Than 300 Coronavirus Cases Are Confirmed - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- How Jair Bolsonaro's Son, Eduardo, Confirmed His Father's Positive Coronavirus Test to Fox News, Then Lied About It - The Intercept [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- De Blasio Resisted on Coronavirus. Then Aides Said Theyd Quit. - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Trump Is Tested for Coronavirus, and Experts Ask: What Took So Long? - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Live Coronavirus Updates and Coverage - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus Threatens Americans With Underlying Conditions - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus Capitalism and How to Beat It - The Intercept [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- An essential reading guide to understand the coronavirus - Vox.com [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- N.Y.C.s Economy Could be Ravaged by Coronavirus Outbreak - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- 'A ticking time bomb': Scientists worry about coronavirus spread in Africa - Science Magazine [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- How coronavirus is affecting the restaurant business, in one chart - Vox.com [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus Map: How To Track Coronavirus Spread Across The Globe - Forbes [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Coronavirus Testing Website Goes Live and Quickly Hits Capacity - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Map: How Many Cases Of Coronavirus Are There In Each US State? : Shots - Health News - NPR [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- Live Coronavirus Updates and Coverage Globally - The New York Times [Last Updated On: March 16th, 2020] [Originally Added On: March 16th, 2020]
- This Is How the Coronavirus Will Destroy the Economy - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Every Star and Public Figure Diagnosed with COVID-19: A Running List - The Daily Beast [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Coronavirus: What you need to know - Fox News [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Travel updates: which countries have coronavirus restrictions and FCO warnings in place? - The Guardian [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Staff angered as Charter prohibits working from home despite spread of coronavirus - TechCrunch [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- If coronavirus scares you, read this to take control over your health anxiety - The Guardian [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- San Francisco and Bay Area will shelter in place to slow coronavirus spread - The Verge [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Coronavirus spreading fastest in UK in London - The Guardian [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Businesses Face a New Coronavirus Threat: Shrinking Access to Credit - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Welcome to Marriage During the Coronavirus - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Sweeping restrictions take effect in coronavirus response as health officials warn US is at a tipping point - CNN [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- How Long Will the Coronavirus Outbreak and Shutdown Last? - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- 201920 coronavirus pandemic - Wikipedia [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Coronavirus - World Health Organization [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- What Is Coronavirus? | HowStuffWorks [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Coronavirus | CISA [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Is there a cure for the new coronavirus? - Livescience.com [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Shelter in Place: Some Residents in Bay Area Ordered to Stay Home - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Tracking the Impact of the Coronavirus on the U.S. - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- 8 Things Parents Should Know About The Coronavirus: Life Kit - NPR [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Spain, on Lockdown, Weighs Liberties Against Containing Coronavirus - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- New Yorks Nightlife Shuttered to Curb Coronavirus - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- How best to fight the economic impact of the coronavirus pandemic - The Guardian [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Heres whos most at risk from the novel coronavirus - The Verge [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Closing Down the Schools Over Coronavirus - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- The U.S. Economy Cant Withstand the Coronavirus by Itself - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- U.S. Lags in Coronavirus Testing After Slow Response to Outbreak - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- U.K. Steps Up Coronavirus Prevention, But Its Hospitals Have Already Been Strained - NPR [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Coronavirus panic is clearing out grocery stores; heres how workers are handling it - Vox.com [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Tracking the Coronavirus: How Crowded Asian Cities Tackled an Epidemic - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Coronavirus Treatment: Hundreds of Scientists Scramble to Find One - The New York Times [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Coronavirus cases have dropped sharply in South Korea. What's the secret to its success? - Science Magazine [Last Updated On: March 17th, 2020] [Originally Added On: March 17th, 2020]
- Facebook was marking legitimate news articles about the coronavirus as spam due to a software bug - The Verge [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- The Single Most Important Lesson From the 1918 Influenza - The New York Times [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- How to Protect Older People From the Coronavirus - The New York Times [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Coronavirus Is Killing Iranians. So Are Trump's Brutal Sanctions. - The Intercept [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Is there a cure for coronavirus? Why Covid-19 is so hard to treat - Vox.com [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Coronavirus: The math behind why we need social distancing, starting right now - Vox.com [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Europeans Erect Borders Against Coronavirus, but the Enemy Is Already Within - The New York Times [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Some of the last people on earth to hear about the coronavirus pandemic are going to be told on live TV - CNN [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Why the US is still struggling to test for the coronavirus - The Verge [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- The Coronavirus Is Here to Stay, So What Happens Next? - The New York Times [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Coronavirus in the U.S. - The New York Times [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Watch the Footprint of Coronavirus Spread Across Countries - The New York Times [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Coronavirus Briefing: What Happened Today - The New York Times [Last Updated On: March 18th, 2020] [Originally Added On: March 18th, 2020]
- Why the Covid-19 coronavirus is worse than the flu, in one chart - Vox.com [Last Updated On: March 21st, 2020] [Originally Added On: March 21st, 2020]
- Fact-Checking 5 Trump Administration Claims On The Coronavirus Pandemic - NPR [Last Updated On: March 21st, 2020] [Originally Added On: March 21st, 2020]
- Trump has scoreboard obsession. It hasnt worked with coronavirus - POLITICO [Last Updated On: March 21st, 2020] [Originally Added On: March 21st, 2020]
- Here's What Is In The 'Families First' Coronavirus Aid Package Trump Approved - NPR [Last Updated On: March 21st, 2020] [Originally Added On: March 21st, 2020]
- Young Adults Come to Grips With Coronavirus Health Risks - The New York Times [Last Updated On: March 21st, 2020] [Originally Added On: March 21st, 2020]
- Which Country Has Flattened the Curve for the Coronavirus? - The New York Times [Last Updated On: March 21st, 2020] [Originally Added On: March 21st, 2020]