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.
“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.
Open and closed
Hong has extensive experience in studying the structures of proteins that are embedded in cell membranes, so when the COVID-19 pandemic began in 2020, she turned her attention to the coronavirus E channel.
When SARS-CoV-2 infects cells, the E channel embeds itself inside the membrane that surrounds a cellular organelle called the ER-Golgi intermediate compartment (ERGIC). The ERGIC interior has a high concentration of protons and calcium ions, which the E channel transports out of ERGIC and into the cell cytoplasm. That influx of protons and calcium leads to the formation of multiprotein complexes called inflammasomes, which induce inflammation.
To study membrane-embedded proteins such as ion channels, Hong has developed techniques that use nuclear magnetic resonance (NMR) spectroscopy to reveal the atomic-level structures of those proteins. In previous work, her lab used these techniques to discover the structure of an influenza protein known as the M2 proton channel, which, like the coronavirus E protein, consists of a bundle of several helical proteins.
Early in the pandemic, Hong’s lab used NMR to analyze the structure of the coronavirus E channel at neutral pH. The resulting structure, reported in 2020, consisted of five helices tightly bundled together in what appeared to be the closed state of the channel.
“By 2020, we had matured all the NMR technologies to solve the structure of this kind of alpha-helical bundles in the membrane, so we were able to solve the closed E structure in about six months,” Hong says.
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.
“We think the side chain conformation of these three regularly spaced phenylalanine residues plays an important role in regulating the closed and open state,” Hong says.
Viral targeting
Previous research has shown that when SARS-CoV-2 viruses are mutated so that they don’t produce the E channel, the viruses generate much less inflammation and cause less damage to host cells.
Working with collaborators at the University of California at San Francisco, Hong is now developing molecules that could bind to the E channel and prevent ions from traveling through it, in hopes of generating antiviral drugs that would reduce the inflammation produced by SARS-CoV-2.
Her lab is also planning to investigate how mutations in subsequent variants of SARS-CoV-2 might affect the structure and function of the E channel. In the omicron variant, one of the hydrophilic, or polar, amino acids found in the pore opening is mutated to a hydrophobic amino acid called isoleucine.
“The E variant in omicron is something we want to study next,” Hong says. “We can make a mutant and see how disruption of that polar network changes the structural and dynamical aspect of this protein.”
News
AI Is Overheating. This New Technology Could Be the Fix
Engineers have developed a passive evaporative cooling membrane that dramatically improves heat removal for electronics and data centers Engineers at the University of California San Diego have created an innovative cooling system designed to greatly enhance [...]
New nanomedicine wipes out leukemia in animal study
In a promising advance for cancer treatment, Northwestern University scientists have re-engineered the molecular structure of a common chemotherapy drug, making it dramatically more soluble and effective and less toxic. In the new study, [...]
Mystery Solved: Scientists Find Cause for Unexplained, Deadly Diseases
A study reveals that a protein called RPA is essential for maintaining chromosome stability by stimulating telomerase. New findings from the University of Wisconsin-Madison suggest that problems with a key protein that helps preserve chromosome stability [...]
Nanotech Blocks Infection and Speed Up Chronic Wound Recovery
A new nanotech-based formulation using quercetin and omega-3 fatty acids shows promise in halting bacterial biofilms and boosting skin cell repair. Scientists have developed a nanotechnology-based treatment to fight bacterial biofilms in wound infections. The [...]
Researchers propose five key questions for effective adoption of AI in clinical practice
While Artificial Intelligence (AI) can be a powerful tool that physicians can use to help diagnose their patients and has great potential to improve accuracy, efficiency and patient safety, it has its drawbacks. It [...]
Advancements and clinical translation of intelligent nanodrugs for breast cancer treatment
A comprehensive review in "Biofunct. Mater." meticulously details the most recent advancements and clinical translation of intelligent nanodrugs for breast cancer treatment. This paper presents an exhaustive overview of subtype-specific nanostrategies, the clinical benefits [...]
It’s Not “All in Your Head”: Scientists Develop Revolutionary Blood Test for Chronic Fatigue Syndrome
A 96% accurate blood test for ME/CFS could transform diagnosis and pave the way for future long COVID detection. Researchers from the University of East Anglia and Oxford Biodynamics have created a highly accurate [...]
How Far Can the Body Go? Scientists Find the Ultimate Limit of Human Endurance
Even the most elite endurance athletes can’t outrun biology. A new study finds that humans hit a metabolic ceiling at about 2.5 times their resting energy burn. When ultra-runners take on races that last [...]
World’s Rivers “Overdosing” on Human Antibiotics, Study Finds
Researchers estimate that approximately 8,500 tons of antibiotics enter river systems each year after passing through the human body and wastewater treatment processes. Rivers spanning millions of kilometers across the globe are contaminated with [...]
Yale Scientists Solve a Century-Old Brain Wave Mystery
Yale scientists traced gamma brain waves to thalamus-cortex interactions. The discovery could reveal how brain rhythms shape perception and disease. For more than a century, scientists have observed rhythmic waves of synchronized neuronal activity [...]
Can introducing peanuts early prevent allergies? Real-world data confirms it helps
New evidence from a large U.S. primary care network shows that early peanut introduction, endorsed in 2015 and 2017 guidelines, was followed by a marked decline in clinician-diagnosed peanut and overall food allergies among [...]
Nanoparticle blueprints reveal path to smarter medicines
Lipid nanoparticles (LNPs) are the delivery vehicles of modern medicine, carrying cancer drugs, gene therapies and vaccines into cells. Until recently, many scientists assumed that all LNPs followed more or less the same blueprint, [...]
How nanomedicine and AI are teaming up to tackle neurodegenerative diseases
When I first realized the scale of the challenge posed by neurodegenerative diseases, such as Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis (ALS), I felt simultaneously humbled and motivated. These disorders are not caused [...]
Self-Organizing Light Could Transform Computing and Communications
USC engineers have demonstrated a new kind of optical device that lets light organize its own route using the principles of thermodynamics. Instead of relying on switches or digital control, the light finds its own [...]
Groundbreaking New Way of Measuring Blood Pressure Could Save Thousands of Lives
A new method that improves the accuracy of interpreting blood pressure measurements taken at the ankle could be vital for individuals who are unable to have their blood pressure measured on the arm. A newly developed [...]
Scientist tackles key roadblock for AI in drug discovery
The drug development pipeline is a costly and lengthy process. Identifying high-quality "hit" compounds—those with high potency, selectivity, and favorable metabolic properties—at the earliest stages is important for reducing cost and accelerating the path [...]
