Chemists discover the structures of open and closed states of the channel, which could help the development of antiviral drugs to reduce inflammation.
MIT researchers have discovered the open structure of the SARS-CoV-2 E channel, complementing their previous findings on its closed state. This research could aid in developing antiviral drugs to block the channel and reduce inflammation in COVID-19.
Understanding the SARS-CoV-2 E Channel
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.
MIT chemists found that the SARS-CoV-2 E protein, which acts as an ion channel, has a broad opening at the bottom when in the closed state and a narrower opening in the open state. Credit: Courtesy of the researchers, MIT News, and iStock
Research Advances
"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 was recently published in the journal Science Advances. MIT postdocs Aurelio Dregni and Pu Duan and graduate student Noah Somberg are also authors of the paper.
Investigating Protein Structures
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.
Structural Insights and Implications
Revealing Atomic-Level Structures
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.
Channel Dynamics and Drug Development
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.
Future Research Directions
Potential for Antiviral Therapies
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."
Reference: "Atomic structure of the open SARS-CoV-2 E viroporin" by João Medeiros-Silva, Aurelio J. Dregni, Noah H. Somberg, Pu Duan and Mei Hong, 13 October 2023, Science Advances.
DOI: 10.1126/sciadv.adi9007
The research was funded by the National Institutes of Health and the MIT School of Science Sloan Fund.
News
Unzipping the Code of Life: Scientists Pinpoint Where DNA First Opens
Researchers mapped where DNA first opens and how a helicase gate may release one strand as genome copying begins. Before a cell can divide, it must open its tightly wound DNA and begin copying the entire [...]
Scientists Tested an 8-Hour Eating Window and Found a Surprising Brain Benefit
Limiting the daily eating window may provide brain benefits beyond those associated with weight loss. Eating within a shorter daily window may provide cognitive benefits beyond those associated with weight loss alone, according to [...]
Focused Ultrasound Opens Blood-Brain Barrier to Treat Brain Cancer
Summary: A new study demonstrates that primary brain tumors (gliomas) are particularly receptive to targeted drug delivery using focused ultrasound (FUS) combined with microbubbles. The team developed a high-resolution MRI protocol to track blood-brain barrier [...]
AI’s promise and practical limits in drug discovery
AI tools are becoming increasingly common in early drug discovery, allowing scientists to analyse data and navigate large volumes of research. However, according to Dr Raminderpal Singh, turning that potential into consistent scientific workflows [...]
GHCE Concept
From the preface of the book Global Health Care Equivalency in the Age of Nanotechnology, Nanomedicine and Artificial Intelligence, Edited by Frank Boehm: Since the publication of my first book (Nanomedical Device and Systems [...]
Healthcare Headlines: Challenges and Advances in 2026
Health-related updates reveal financial adjustments by Universal Health Services due to Medicaid reimbursement uncertainties, significant pollution-linked health concerns from French-British oil firm Perenco in Congo, drug trial setbacks, potential restructuring at major medical firms, [...]
Scientists Discover the Brain Protein That Helps Alzheimer’s Spread Through the Brain
Scientists have identified a brain protein that may help Alzheimer’s spread, revealing a potential new target for slowing the disease’s progression. Alzheimer’s disease is closely linked to the accumulation of a toxic form of the protein [...]
How Immune Dysregulation Contributes to Psychiatric Disorders
Introduction Growing evidence suggests that disruptions in immune function may play an important role in the development and progression of psychiatric disorders. However, immune mechanisms probably contribute more strongly in some patients than others, [...]
Electrostatic Discharge Boosts Triboelectric Nanogenerator Current and Enables DC Output
Controlled electrical discharges could enable triboelectric nanogenerators to achieve higher peak currents, extending nano-enabled energy harvesting into chemical processing and self-powered sensing. Paper: Electrostatic discharge as a breakthrough strategy for triboelectric nanogenerators. A new review [...]
Swiss laboratory uses old drugs against rare diseases
Researchers at the University of Geneva are combing through collections of approved drugs to find new therapies for rare diseases – with some success. This approach is gaining traction around the world, while pharmaceutical [...]
Nanozyme Aptasensors Show Promise for Faster Food, Health, and Environmental Testing
By pairing robust artificial enzymes with highly selective aptamers, nanozyme aptasensors could help detect disease biomarkers, pathogens, and contaminants faster, but the review shows that real-world deployment still depends on overcoming matrix interference, biofouling, [...]
Paralyzed Man Feels Sensation Again With Brain Stimulation Device
Aneuroprosthetic system has allowed a man with paralysis to grasp and lift objects and feel touch again. The device helped 42-year-old Keith Thomas of Massapequa, New York, who was paralyzed from the chest down [...]
Global Cancer Cases Could Surge 67% by 2050, New Report Warns
New data reveal major geographic disparities and highlight the urgent need for global action on prevention, early detection, and equitable access to treatment. For roughly one in five people worldwide, cancer will become part [...]
A Deadly Ebola-Like Virus Is Spreading. Are We Ready?
BU virologist Nancy Sullivan says the Bundibugyo outbreak in the Democratic Republic of the Congo underscores the need for broader outbreak preparedness. The death of a nurse marked the moment health officials recognized that [...]
Why Most Animal Viruses Never Become Human Pandemics
From receptor mismatch to risky human-animal interfaces, this article explains why spillover is common but true pandemic emergence remains rare. Introduction Humans are constantly exposed to animal viruses through farming, wildlife contact, and the [...]
Stem cell organoids repair heart microvessels in coronary artery disease models
A Stanford University team has shown that vascular organoids derived from human stem cells can repair the heart’s microvessel network in pigs with ischaemic heart disease – a proof-of-concept advancement that could open new therapeutic [...]
