3-D protein modeling suggests why COVID-19 infects some animals, but not others

3D protein modeling suggests why COVID-19 infects some animals, but not others
3D structure model of the receptor-binding domain of SARS-CoV-2 (in blue) interacting with the human ACE2 receptor (in gray). Amino acids important to the interaction, which are present only in COVID-susceptible animal species are highlighted in yellow. Sugars bound to the proteins are shown in pink. Credit: Rodrigues et al. 2020 (CC-BY 2.0)

Some animals are more susceptible to COVID-19 infection than others, and new research suggests this may be due to distinctive structural features of a protein found on the surface of animal cells. João Rodrigues of Stanford University, California, and colleagues present these findings in the open-access journal PLOS Computational Biology.

Previous research suggests that the current pandemic began when the virus that causes COVID-19, SARS-CoV-2, jumped from bats or pangolins to humans. Certain other animals, such as cattle and cats, appear to be susceptible to COVID-19, while others, such as pigs and chickens, are not. One zoo even reported infections in tigers. However, it was unclear why some animals are immune and others are not.

To address this question, Rodrigues and colleagues looked for clues in the first step of infection, when SARS-CoV-2’s “spike” protein binds to an “ACE2” receptor protein on the surface of an animal cell. They used computers to simulate the proteins’ 3-D structures and investigate how the spike protein interacts with different animals’ ACE2 receptors—similar to checking which locks fit a certain key.

The researchers found that certain animals’ ACE2 “locks” fit the viral “key” better, and that these animals, including humans, are susceptible to infection. Despite being approximations, the simulations pinpointed certain structural features unique to the ACE2 receptors of these susceptible species. The analysis suggest that other species are immune because their ACE2 receptors lack these features, leading to weaker interactions with spike proteins.

These findings could aid development of antiviral strategies that use artificial “locks” to trap the virus and prevent it from interacting with human receptors. They could also help improve models to monitor animal hosts from which a virus could potentially jump to humans, ultimately preventing future outbreaks.

“Thanks to open-access data, preprints, and freely available academic software, we went from wondering if tigers could catch COVID-19 to having 3-D models of protein structures offering a possible explanation as to why that is the case in just a few weeks,” Rodrigues says.

His team plans to continue refining the computational tools used in this study.

Dozens of mammals could be susceptible to SARS-CoV-2

More information:
Rodrigues JPGLM, Barrera-Vilarmau S, M. C. Teixeira J, Sorokina M, Seckel E, Kastritis PL, et al. (2020) Insights on cross-species transmission of SARS-CoV-2 from structural modeling. PLoS Comput Biol 16(12): e1008449. doi.org/10.1371/journal.pcbi.1008449
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Protein molecules in cells function as miniature antennas

Protein molecules in cells function as miniature antennas
A crystal of a red fluorescent protein placed in a combined instrument consisting of a fluorescence microscope and an X-ray diffractometer. The crystal glows red when illuminated by a blue laser beam. Credit: Petr Pachl / IOCB Prague

Researchers led by Josef Lazar of the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague) have demonstrated that molecules of fluorescent proteins act as antennas with optical properties (i.e. the ability to absorb and emit light) dependent on their spatial orientation. First discovered in jellyfish, fluorescent proteins are nowadays widely used in studies of molecular processes in living cells and organisms. The newly described properties of these molecules will find applications in basic biological research as well as in novel drug discovery. A team of researchers from IOCB Prague, the Institute of Microbiology, and the Institute of Molecular Genetics of the Czech Academy of Sciences has published the findings in the journal Proceedings of the National Academy of Sciences.

To achieve these results, the researchers produced sufficient amounts of fluorescent proteins by using genetically modified bacteria, identified the conditions under which the proteins form crystals, and determined the atomic structure of the crystals. Employing a unique microscope developed within the group, they then measured how these crystals absorb and emit light, and from the data they calculated the directional properties of the individual molecules. This allowed them to verify that the fluorescent protein molecules do not behave as tiny luminescent dots, as they are often mistakenly assumed, but rather as miniature antennas. Much like antennas for radio, WiFi, and television transmission, these molecules only absorb light from certain directions. Likewise, they only emit light in certain directions. The researchers also succeeded in precisely establishing these directions.

The possibility of fluorescent protein molecules behaving as antennas capable of absorbing extraneous light had been assumed, but it long proved difficult to confirm, and that limited its applications. The obstacles have been overcome by Josef Lazar of IOCB Prague and his team, which specializes in the development and use of advanced optical microscopy methods.

Protein molecules in cells function as miniature antennas
A crystal of a red fluorescent protein placed in a combined instrument consisting of a fluorescence microscope and an X-ray diffractometer. The crystal glows red when illuminated by a blue laser beam. Credit: Petr Pachl / IOCB Prague

“Based on the findings of other laboratories and our own, we suspected that fluorescent protein molecules likely behaved as antennas. Nonetheless, we were surprised to see just how true that analogy is and how accurately we were able to establish the directions from which these molecules absorb light and emit it,” says Josef Lazar.

The fact that fluorescent protein molecules function as miniature antennas is interesting not only as a curiosity of physics—it can also have important practical applications. Attaching a fluorescent protein to some other protein of interest means attaching a miniature antenna to it that can then be used to establish, in detail, changes in the shape of the molecules of the protein of

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DeepMind AI breakthrough in protein folding will accelerate medical discoveries


An illustration of the possible structure of a “membrane protein” associated with the coronavirus, according to a model created by DeepMind’s AlphaFold program. 


DeepMind, a division of Alphabet, says it has solved one of the most difficult computing challenges in the world: predicting how protein molecules will fold. It is key to understanding important biological processes and treating diseases such as COVID-19.

The London-based organization said that its claims of a breakthrough had been verified by organizers of a competition held every two years to test computer models, the Critical Assessment of protein Structure Prediction (CASP). 

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DeepMind named its protein folding prediction system AlphaFold and said that the latest version has been four years in development. 

Writing on its blog, the AlphaFold team described the success of the system being due to methods that “draw inspiration from the fields of biology, physics, and machine learning, as well as of course the work of many scientists in the protein folding field over the past half-century.”

There are about 180 million known proteins but only about 170,000 protein structures have been mapped through X-ray crystallography and other techniques. X-ray crystallography is how DNA’s double-helix of amino acids structure was discovered and the structure revealed how it copied itself. But it can take months and sometimes years to determine a protein structure.

Complicated chains of amino acids can have vast numbers of permutations. Yet in nature proteins will only fold into a very specific shape and that shape determines its role in biological processes, including in viruses. 

Professor Andrei Lupas, Director of the Max Planck Institute for Developmental Biology, writing on the DeepMind blog: “AlphaFold’s astonishingly accurate models have allowed us to solve a protein structure we were stuck on for close to a decade, relaunching our effort to understand how signals are transmitted across cell membranes.”

DeepMind’s approach is ideal for membrane proteins which cannot be easily crystalized. 

The AlphaFold team said that in March it predicted two protein structures of SARS-CoV-virus, which had been separately identified months later by researchers. This shows its potential applications in predicting the shape of mutated viruses.

The CASP competition evaluates competing models of prediction by measuring the variation from actual structure in Angstroms — the width of an atom. Competitors analyze samples of proteins whose structure has never been published.  

Units called Global Distance Test (GDT) are used to evaluate each protein structure prediction. A score of 90 GDT or above is considered equal to experimental analysis. AlphaFold’s median score against all target proteins was 92.4 GDT.

What is additionally impressive about this achievement is the seemingly small amount of data AlphaFold was trained on. With only some 170,000 known protein structures in public databases AlphaFold had to determine the rules for a complex structure from very little information.

AlphaFold’s training was very fast compared

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MIT researchers uncover molecular structure of a protein found in COVID-19

“Our findings could be useful for medicinal chemists to design alternative small molecules that target this channel with high affinity,” said Mei Hong, an MIT chemistry professor and senior author of the research team’s new study, in the statement.

The paper from Hong’s team was published Nov. 11 in the journal Nature Structural and Molecular Biology. Its lead author was MIT graduate student Venkata Mandala, the statement said, and additional authors were MIT postdoc Matthew McKay, along with graduate students Alexander Shcherbakov and Aurelio Dregni, as well as Antonios Kolocouris, a pharmaceutical chemistry professor at the University of Athens.

At the outset of the pandemic, the statement said, Hong and her students decided to focus their efforts on one of the COVID-19 proteins. They settled on protein E, the statement said, partly because it’s similar to an influenza protein called the M2 proton channel, which Hong’s studied previously.

“We determined the influenza B M2 structure after about 1.5 years of hard work, which taught us how to clone, express, and purify a virus membrane protein from scratch, and what NMR [nuclear magnetic resonance] experimental strategies to take to solve the structure of a homo-oligomeric helical bundle,” Hong said in the statement. “That experience turned out to be the perfect training ground for studying SARS-CoV-2 E.”

The researchers cloned and purified the E protein in two and a half months, according to the statement. To determine the protein’s structure, the statement said, researchers embedded it into a lipid bilayer, similar to a cell membrane, and analyzed it with NMR.

The statement noted that the COVID-19 E protein looks nothing like the ion-channel proteins of the influenza and HIV-1 viruses. The difference, the statement said, is among the topics that Hong and her team will study in the future.

“This paper represents a clear step forward, reporting the first high-resolution structure of a channel domain formed by any member of the coronavirus envelope protein family, and opens the way to rationally design compounds to block envelope protein channel activity,” said Jaume Torres, an associate professor of biological sciences at Nanyang Technological University in Singapore, in the statement.

Torres wasn’t involved in the research, according to MIT.

The MIT statement said the researchers also found that two drugs, amantadine and hexamethylene amiloride, can block the entrance of the E channel, but they bind only “weakly” to the protein.

Stronger inhibitors, the statement said, could emerge as potential drug candidates for treating COVID-19.

“Even when the pandemic is over, it is important that our society recognizes and remembers that fundamental scientific research into virus proteins or bacterial proteins must continue vigorously, so we can preempt pandemics,” Hong said in the statement. “The human cost and economic cost of not doing so are just too high.”

Travis Andersen can be reached at [email protected] Follow him on Twitter @TAGlobe.

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The Global Protein Expression Market is expected to grow by USD 1.63 bn during 2020-2024, decelerating at a CAGR of 14% during the forecast period

Global Protein Expression Market 2020-2024 The analyst has been monitoring the protein expression market and it is poised to grow by USD 1. 63 bn during 2020-2024, decelerating at a CAGR of 14% during the forecast period.

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The report offers an up-to-date analysis regarding the current global market scenario, the latest trends and drivers, and the overall market environment. The market is driven by the increasing advances in proteomics research and the rise in the usage of protein expression in the food industry. In addition, increasing advances in proteomics research are anticipated to boost the growth of the market as well.
The protein expression market analysis includes the solution segment and geographical landscapes.

The protein expression market is segmented as below:
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• Products
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• North America
• Europe

This study identifies the increase in chronic diseases as one of the prime reasons driving the protein expression market growth during the next few years.

The analyst presents a detailed picture of the market by the way of study, synthesis, and summation of data from multiple sources by an analysis of key parameters. Our report on the protein expression market covers the following areas:
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Discovery of pH-dependent ‘switch’ in interaction between pair of protein molecules

Discovery of pH-dependent 'switch' in interaction between pair of protein molecules
Upper panel: the different interaction sites observed by NMR under different pH conditions. Lower panel: the crystal structures of the complex under two pH conditions have different binding-sites Credit: FENG Yingang

All biological processes are in some way pH-dependent. Human bodies and those of other organisms need to maintain specific and constant pH regulation in order to function. Changes in pH can have serious biological consequences—or serious benefits, as researchers at the Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT), Chinese Academy of Sciences (CAS) found.

The findings are published on Oct. 23 in the journal Science Advances.

Cellulosomes are extracellular complexes consisting of multiple enzymes, which are associated with the cell’s surface. Within the cellulosome cellular structure, the protein molecules dockerin and cohesin were the focus of this study.

“Cellulosomes are complex nanomachines in nature and have great values in biofuel production and biotechnology. This study is an example of the complexity and diversity of cellulosomes,” said study author Feng Yingang, Professor, Metabolomics Group.

Changes in pH have previously been shown to result in “on-off” switches within protein functions, many of which occur naturally and are essential for life processes. Biotechnical innovations can utilize this relevant phenomenon to develop sensors or switches using biomolecules that are pH-dependent.

The latest discovery, on the cellulosome assembly of the bacterium Clostridium acetobutylicum, takes this prospect further by switching between two functional sites, rather than simply on or off. This opens additional possibilities.

“Our study not only revealed an elegant example of biological regulation but also provides a new approach for developing pH-dependent protein devices and biomaterials for biotechnological application,” said Feng.

Researchers found that changing the pH from 4.8 to 7.5 resulted in the cohesin-binding sites on the dockerin molecule switching from one site to the other. This type of switching between two functional sites has not been noted for any interaction between proteins previously.

Nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) were used to describe the distinct features of this interaction. Researchers additionally noted that the affinity, or the attraction between the molecules, was found to change along with the pH. This property is considered unusual when compared to other cohesin-dockerin interactions and is unique, thus far, to C. acetobutylicum bacteria.

These, and future discoveries like it, can potentially be used to create more complex biological switches in synthetic biology and further developments in the fields of biotechnology.

“Next, we will continue to elucidate the structure and regulation of cellulosomes, which could provide interesting novel discoveries and new strategies to increase the efficiency of lignocellulose-based biofuel production,” Feng said. “Our ultimate goal is to promote sustainable and economical lignocellulose bioconversion and bioenergy production.”

Structural and functional mechanisms of a new class of bacterial sigma/anti-sigma factors revealed

More information:
“Discovery and mechanism of a pH-dependent dual-binding-site switch in the interaction of a pair of protein modules” Science Advances (2020). DOI: 10.1126/sciadv.abd7182
Provided by
Chinese Academy of Sciences

Discovery of pH-dependent ‘switch’ in interaction between pair of protein

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