Coronavirus protein found to cut off key immune pathway
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Coronavirus protein found to cut off key immune pathway
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Coronavirus protein found to cut off key immune pathway.
Powerful X-rays from the SLAC synchrotron show that the basic function of our immune system can’t beat the SARS-CoV-2 protein.
Scientists have intensively studied the SARS-CoV-2 virus over the past two years, laying the groundwork for a COVID-19 vaccine and antiviral treatment.
Researchers at the Department of Energy’s SLAC National Accelerator Laboratory have now for the first time seen one of the virus’s most critical interactions, which could help develop more precise treatments.
This image shows two chains of Mpro, the main protease of the SARS-CoV-2 virus, and a human protein called NEMO.
One NEMO chain (blue) has been severed by Mpro, while the other NEMO chain (red) is being severed by Mpro.
Without NEMO, the immune system would be slower to respond to increasing viral loads or new infections.
Seeing how Mpro attacks NEMO at the molecular level may inspire new therapeutic approaches.
The researchers captured what happens when a viral protein called Mpro chops off a protective protein called NEMO in an infected person.
Without NEMO, the immune system is slower to respond to growing viral loads or new infections.
Understanding how Mpro targets NEMO at the molecular level may provide new therapeutic strategies.
The researchers exposed crystal samples of the protein complex to intense X-rays from SLAC’s Stanford Synchrotron Radiation Light Source (SSRL) to see how Mpro cleaved NEMO.
The protein samples were hit by X-rays, showing what Mpro looked like when it deprived NEMO of its primary function of facilitating communication with the immune system.
This image shows how SARS-CoV-2 Mpro recognizes and cleaves NEMO, a crystal structure determined from a powerful X-ray beam from SSRL beam 12-2. Source: SLAC National Accelerator Laboratory
“We saw that viral proteins cut NEMO as easily as sharp scissors cut tissue paper,” said co-first author Soichi Wakatsuki, SLAC and Stanford professor. “Imagine the bad things that happen when the good proteins in our bodies start to be cut into pieces.” Image from SSRL provides first structure of SARS-CoV-2 Mpro bound to human protein and shows NEMO The exact location of the cut.
SSRL lead scientist and co-author Irimpan Mathews said: “If you can block the site where Mpro binds to NEMO, you can stop this cleavage from happening again and again. Blocking Mpro can delay the rate at which the virus takes over the body. Solving the crystal structure revealed that Mpro The binding site is the first step in blocking the protein.”
A team of researchers from SLAC, DOE’s Oak Ridge National Laboratory, and other institutions recently published their results in the journal Nature Communications.
Protect an immune pathway
NEMO is part of the human immune system known as the NF-κB pathway. You can think of the NEMO and NF-κB pathways as card readers and wiring outside the entrance door to a locked building.
If the wire to the card reader is cut, the door won’t open, which means a person (or an immune system activator like NEMO) is stuck outside and can’t do what they came to do.
Researchers group photo From left: Mikhail Hameedi, SLAC scientist and co-first author; Soichi Wakatsuki, co-first author, professor at SLAC and Stanford University; Irimpan Mathews, SSRL chief scientist and co-author. Source: Jacqueline Ramseyer Orrell/SLAC National Accelerator Laboratory
The NF-κB pathway is a key part of the protective inflammatory response.
When NEMO is cut off, our immune response cannot be activated, resulting in various adverse effects on our bodies. If Mpro disrupts NEMO, helping the virus evade our innate immune response, the COVID-19 viral infection could get worse.
In addition, a separate study conducted by researchers at the German institution found that the loss of NEMO by the action of Mpro may lead to damage to certain brain cells, causing the neurological symptoms observed in COVID-19 patients, the researchers said.
One drug currently approved for emergency use targets the Mpro protein by delivering Mpro inhibitors to infected people. Now that the cleavage site of NEMO has been observed, this inhibitor drug can be boosted.
“The crystal structures of NEMO and Mpro gave us targets to develop treatments that prevent these cuts from happening,” said SLAC scientist and co-first author Mikhail Ali Hameedi. “While current antiviral drugs can target Mpro, seeing the molecular details of how Mpro attacks NEMO will help us develop new treatments in the future when Mpro mutates.”
Finding ways to improve antiviral inhibitors is especially important for SARS-CoV-2.
Among coronaviruses—including the original SARS-CoV and MERS-CoV viruses—the Mpro of SARS-CoV-2 was most effective at attaching and severing NEMO.
SARS-CoV-2’s Mpro grips more tightly than its counterparts from other coronaviruses, and may be chopping hundreds of other key proteins in human host cells, such as those associated with blood disorders, the researchers said.
To predict how well Mpro bound to NEMO, the researchers used the Summit supercomputer at the Oak Ridge Leadership Computing Facility.
Combining molecular dynamics simulations with five machine learning models in a novel way and applying quantum chemistry, they found that Mpro may have the highest binding affinity among SARS-CoV-2 compared to other major coronaviruses.
In previous studies, these techniques helped scientists narrow down the list of potential antiviral inhibitor drugs.
“Using a suite of computational methods, we were able to predict the strongest binding point between NEMO and Mpro,” said co-first author Erica Prates, an ORNL scientist. “We believe that the high binding affinity of these hotspots helps explain the virus’ high fitness in humans.”
In the future, the biomedical industry could use this research to help build better inhibitor drugs and understand how other proteins are affected by Mpro, Wakatsuki said.
“NEMO is just the tip of the iceberg,” he said. “We can now study what happens when many other proteins in the body are cleaved by Mpro in vivo,” he said.
Coronavirus protein found to cut off key immune pathway
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