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Structural differences between SARS-CoV-1 and SARS-CoV-2 RBDs

Jacob Scott

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The genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is about 80% similar to that of SARS-CoV. This high degree of similarity shared between these two viruses has led many to wonder why SARS-CoV-2 is so much more infectious and transmissible as compared to SARS-CoV.

A new Cells journal study compares the SARS-CoV-2 receptor-binding domain (RBD) (RBDCoV2) to the SARS-CoV RBD (RBDCoV) using computational methods to understand the binding affinities of the two proteins to the human receptor angiotensin-converting enzyme 2 (ACE2) receptor.

Study: Mechanistic Origin of Different Binding Affinities of SARS-CoV and SARS-CoV-2 Spike RBDs to Human ACE2. Image Credit: Cinefootage Visuals / Shutterstock.com

SARS-CoV-2 spike protein

Both SARS-CoV and SARS-CoV-2 utilize the ACE2 receptor for cell entry through their viral spike protein. The spike protein consists of three identical protomers that protrude from the lipid surface of the virus. Each protomer has two subunits known as S1 and S2. Whereas S1 is responsible for virus attachment to cells, S2 facilitates the fusion of the viral and cellular membranes.

The N-terminal domain (NTD) and C-terminal domain (CTD) of the S1 subunit fold independently as two large domains. The CTD acts as the RBD.

The SARS-CoV-2 RBD is the current target for coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) and adenovirus-based vaccines because it is majorly targeted by the immune response.

Spike protein dynamics

The spike protein trimer is not a rigid entity and instead presents different conformations or states. Moreover, this protein can present in a closed state, where all RBDs are in the down orientation and buried in the trimer. Comparatively, the spike protein can also present in an open state where one, two, or three RBDs are in the erect conformation. These orientations can coexist in equilibrium and be distributed within the spike population.

In the closed conformation, the spike protein cannot bind ACE2. A hinge-like motion progressively opens RBDs and allows ACE2 binding.

After binding of the first RBD to ACE2, the open conformation is stabilized and promotes the opening of the other two RBDs. These two RBDs now bind ACE2 in a fully open configuration, which further primes S2 unsheathing and results in membrane fusion.

Structures of the RBDCoV-ACE2 and RBDCoV2-ACE2 complexes and sequence alignment of RBDCoV and RBDCoV2. (A,B) Cartoon representations of the complete complex structures of RBDCoV-ACE2 (modeled based on the crystal structure with PDB ID 2AJF and RBDCoV2-ACE2 (PDB ID: 6M0J respectively. ACE2 is colored gray, with Zn2+ and Cl- ions represented as spheres in yellow and green, respectively; cores and RBMs of both RBDs are colored cyan and red, respectively. (C) Backbone superposition of RBDCoV-ACE2 (red) and RBDCoV2-ACE2 (green). (D) Structure-based sequence alignment of RBDCoV and RBDCoV2. The identical residues are white on a red background and the similar residues are red on a white background; the negatively and positively charged residues are indicated by red and blue triangles, respectively. The ACE2-contacting residues (or RBD interface residues) identified in this work are indicated by black dots; RBM (residues 438-506 according to residue numbering of RBDCoV2) is highlighted by enclosure with a red box.

RBD structure and function

The opening of the RBD is a prerequisite for ACE2 binding. Even so, RBD is an independently folded domain and its opening has very little effect on the overall conformation.

Previous computational studies have shown that certain mutations outside the RBD can influence ACE2-binding affinity by altering the spike conformational dynamics. Yet, ACE2-binding affinity is usually evaluated using the RBD, rather than the spike trimer.

Several experimental and computational studies have shown that the ACE2-binding affinity of RBDCoV2 is higher than that of RBDCoV. Due to this greater binding affinity, SARS-CoV-2 has increased infectivity and transmissibility as compared to SARS-CoV.

RBDCoV and RBDCoV2 crystal structures in complex with human ACE2 reveal that the RBDs share similar overall conformations and nearly identical modes of ACE2 binding. Both RBDs have a core and a receptor-binding motif (RBM) subdomains.

The core has a twisted five-stranded antiparallel ?-sheet that is connected by short helices and loops and contains few amino acids that encounter ACE2. The RBM has a short two-stranded antiparallel ?-sheet, two short helices, and several long loops and contains most of the amino acids that make contact with ACE2.

RBDCoV and RBDCoV2 are 73.2% identical, whereas their cores are 88.0% identical and their RBMs are 47.8% identical. This may explain the different ACE2-binding affinities of RBDCoV and RBDCoV2, as the RBM has more ACE2-contacting amino acids.

About the study

The current study explores the mechanistic origin of the difference in the ACE2-binding affinities of RBDCoV and RBDCoV2. Molecular dynamics simulations were performed on the structures of RBD-ACE2 complexes of SARS-CoV and SARS-CoV-2.

Additionally, the researchers also conducted comparative dynamics and thermodynamics analyses, calculations of the protein-protein and per-residue binding free energies (BFEs), constructions of the interface residue contact networks (IRCNs), and comprehensive comparative analyses of IRCNs, interface interactions, and BFE components of individual amino acids.

Study findings

As compared to the RBDCoV2-ACE2 complex, RBDCoV-ACE2 demonstrates enhanced dynamics and inter-protein positional movements, as well as increased conformational entropy and conformational diversity. The inter-protein electrostatic attractive interactions primarily determine the high ACE2-binding affinities. Notably, the ACE2 and RBDCoV2 exhibit significantly enhanced electrostatic attractive interactions as compared to their interaction with RBDCoV.

The amino acid changes at the RBD interface are responsible for the overall stronger inter-protein electrostatic attractive force in RBDCoV2-ACE2. This tightens the interface packing and suppresses the dynamics of RBDCoV2-ACE2, as well as enhances the ACE2-binding affinity of RBDCoV2.

Since the RBD amino acid changes resulting in gain/loss of the positive/negative charges can greatly affect binding affinity, SARS-CoV-2 variants harboring such mutations warrant special attention, particularly those close to or at the binding interfaces of ACE2.

Conclusions

The current study provides new insights into the dynamics and energetics of the mechanisms of RBD-ACE2 interactions. Furthermore, the study findings explain an increased RBDCoV2-ACE2-binding affinity than that of RBDCoV.

Journal reference:
Zhang, Z., Xia, Y., Shen, J., et al. (2022) Mechanistic Origin of Different Binding Affinities of SARS-CoV and SARS-CoV-2 Spike RBDs to Human ACE2. Cells 11(8):1274. doi:10.3390/cells11081274.

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Unraveling How Strigoractone Hormone Regulates Massive Gene Networks Controlling Plant Growth

Jacob Scott

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As sessile organisms, plants have to continually adapt their growth and architecture to the ever-changing environment. To do so, plants have evolved distinct molecular mechanisms to sense and respond to the environment and integrate the signals from outside with endogenous developmental programs.

New research from Nitzan Shabek’s laboratory at the UC Davis College of Biological Sciences, published in Nature Plants, unravels the underlying mechanism of protein targeting and destruction in a specific plant hormone signaling pathway.

Our lab aims at deciphering sensing mechanisms in plants and understanding how specific enzymes function can be regulated at the molecular levels. We have been studying a new plant hormone signal, strigolactone, that governs numerous processes of growth and development including branching and root architecture.”

Nitzan Shabek, assistant professor of biochemistry and structural biology, Department of Plant Biology

The work stems from a study by Shabek, published in Nature in 2018, unravelling molecular and structural changes in an enzyme, MAX2 (or D3) ubiquitin ligase. MAX2 was found in locked or unlocked forms that can recruit a strigolactone sensor, D14, and target for destruction a DNA transcriptional repressor complex, D53. Ubiquitins are small proteins, found in all eukaryotes, that “tag” other proteins for destruction within a cell.

To find the key to unlock MAX2 and to better understand its molecular dynamics in plants, postdoctoral fellows Lior Tal and Malathy Palayam, with junior specialist Aleczander Young, used an approach that integrated advanced structural biology, biochemistry, and plant genetics.

“We leveraged structure-guided approaches to systemically mutate MAX2 enzyme in Arabidopsis and created a MAX2 stuck in an unlocked form”, said Shabek, “some of these mutations were made by guiding CRISPR/Cas9 genome editing thus providing us a discovery platform to study and analyze the different signaling outputs and illuminate the role of MAX2 dynamics.”


They found that in the unlocked conformation, MAX2 can target the repressor proteins and biochemically decorate them with small ubiquitin proteins, tagging them for destruction. Removing these repressors allows other genes to be expressed – activating a massive gene network that governs shoot branching, root architecture, leaf senescence, and symbiosis with fungi, Shabek said.

Sending these repressors to the proteasome disposal complexes requires the enzyme to relock again. The team also showed that MAX2 not only target the repressors proteins, but once it is locked the strigolactone sensor itself gets destroyed, returning the system to its original state.

Finally, the study uncovered the key to the lock, an organic acid metabolite that can directly trigger the conformational switch.

“Beyond the implication in plants signaling, this is the first work that placed a primary metabolite as a direct new regulator of this type of ubiquitin ligase enzymes and will open new avenues of study in this direction,” Shabek said.

Additional coauthors on the paper are specialist Mily Ron and Professor Anne Britt, Department of Plant Biology. The study was supported by NSF CAREER and EAGER grants to Shabek. X-ray crystallography data was obtained at the Advanced Light Source, Lawrence Berkeley National Laboratory, a U.S. Department of Energy user facility.

Source:
Journal reference:

Tal, L., et al. (2022) A conformational switch in the SCF-D3/MAX2 ubiquitin ligase facilitates strigolactone signalling. Nature Plants. doi.org/10.1038/s41477-022-01145-7.

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UrFU Sociologists Identify Digital Fears Among Young People

Jacob Scott

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Sociologists at the Ural Federal University (UrFU) have identified digital fears among young people. According to experts, these are additional fears that do not replace, but complement and reinforce traditional ones. They emerged against the background of uncertainty, the growth of forces beyond human control. Developed emotional intelligence, creativity, and the ability to collaborate help to overcome them.

In the study, sociologists interviewed 1,050 people aged 18-30. Respondents were asked to assess which digital risks concern them most. The study was launched in 2020 and the results were published in April 2022 in the Changing Societies & Personalities journal.

The first group of fears is influence and control. It touches on the problem of interference with privacy by technical means. This category is the most significant for young people: 55.8% are afraid of total control by means of video-surveillance and monitoring software on their mobile devices. 48.5% of respondents believe they are at risk of wiretapping, tracking content in social networks, and inability to keep correspondence secret.”

Natalia Antonova, Professor, Department of Applied Sociology, UrFU

45.8% of young people fear the manipulative influence of the media and an increase in fake news. At the same time, only 27.8% and 18.1% of respondents are concerned about microchipping and genetic manipulation, respectively. It is likely that these threats seem more controllable, both from the individual (through control of food choices, medical procedures, etc.) and from government programs, the researchers believe.

The second group of concerns is crime and security. Here young people are wary of illegal actions using digital technology.

“One of the main fears of 56% of young people is the security of personal data. This is related both to the growth of personal information in social networks and messengers, and to the growth of hacker attacks and viruses. 42.9% of young citizens are afraid of Internet fraudsters, and 25.8% are afraid of losing important information, including smashing their phones, not saving data, forgetting their passwords, or being without an Internet connection,” explains Sofia Abramova, Associate Professor at the Department of Applied Sociology at UrFU.

The third group of fears is based on changes in the way and pace of life, ways of interaction. Thus, 28.4% of respondents indicate a constant lack of time, the acceleration of communications, and worries about not being able to complete all tasks in time. Respondents are also concerned about the growth of online communications and communications with electronic systems (bots, autoresponders, product systems, etc.).

“As a result, 15.3% of young people raise problems related to increasing social distrust against the background of increasing dependence of human life and health on other people and electronic systems: in public transport, planes, elevators, medical intervention,” explains Sofia Abramova.

Respondents also fear the negative consequences of technological development. For example, 22.2% of young citizens fear the robotization of labor processes and the displacement of humans by robots. 14.6% speak directly about negative emotions in relation to the expansion of artificial intelligence.

The fifth type of fear is social inequality. Young people negatively assess the growth of inequality in access to information resources and technology, the exclusion of citizens from the economy depending on the level of digital competence and education, and age. As a result, they fear that benefits will be distributed more and more unequally, both among the inhabitants of the country and between countries.

“It is noteworthy that young people are simultaneously afraid of total surveillance via phone and afraid of being left without mobile devices. Fears shape the irrational behavior of the digital generation, entailing serious transformations in everyday life,” says Natalia Antonova.

Source:
Journal reference:

Abramova, S.B., et al. (2022) Digital Fears Experienced by Young People in the Age of Technoscience. Changing Societies & Personalities. doi.org/10.15826/csp.2022.6.1.163.

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Study demonstrates increased incidence of SARS-CoV-2 Omicron breakthrough infection in cancer patients

Jacob Scott

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In a recently published article in the journal Cancer Cell, scientists have demonstrated the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients residing in Austria and Italy. The study reveals an induction in Omicron breakthrough infections in patients with hematologic and solid cancers.

Study: Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron. Image Credit: Lightspring/Shutterstock

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, has been found to cause severe infections in immunocompromised patients, including cancer patients. Moreover, a relatively lower level of neutralizing antibodies in response to COVID-19 vaccines has also been observed in cancer patients, especially those receiving B cell-targeting therapies.

The emergence of SARS-CoV-2 variants with improved immune fitness, such as delta and Omicron variants, has caused a sharp increase in breakthrough infections even in fully vaccinated individuals. However, the vaccines still show high protective efficacy against severe and fatal infections. COVID-19 vaccines have shown acceptable efficacy against severe disease, even in Omicron-infected cancer patients. However, the isolation and quarantine measures associated with SARS-CoV-2 infection may impair the routine administration of anticancer therapy, which can reduce the survival prognosis in cancer patients.

In the current study, the scientists have assessed the incidence of SARS-CoV-2 infection in cancer patients throughout the pandemic.

Study design

The study included 3,959 cancer patients, of whom 77% had solid cancer, and 23% had hematologic cancer. About 69% of the patients did not receive any anticancer treatment at the time of COVID-19 vaccination. Regarding vaccine coverage, about 85% of the patients had received at least one vaccine dose, and 15% remained unvaccinated. The incidence of SARS-CoV-2 infection in these patients was assessed between February 2020 and 2022.

Important observations

SARS-CoV-2 infection was detected in about 24% of the patients during the study period. During the delta-dominated wave, vaccine breakthrough infection was observed in 43% of the patients. In contrast, a significantly higher percentage of breakthrough infection (70%) was observed among the patients during the Omicron-dominated wave. During both delta and Omicron waves, cancer patients receiving systemic anticancer treatment showed a significantly higher percentage of breakthrough infection than those not receiving treatment (83% vs. 56%).

Regarding disease severity irrespective of vaccination status, a higher frequency of COVID-19-related hospitalization was observed during the delta wave compared to that during the Omicron wave. However, a relatively shorter duration of hospital stay was observed in vaccinated patients compared to that in unvaccinated patients. In addition, only 9% of patients with breakthrough infections were admitted to the intensive care unit (ICU). This highlights the protective efficacy of COVID-19 vaccines against severe disease.

Humoral immune response to vaccination

To determine vaccine-induced antibody response against delta and Omicron variants, the scientists measured blood levels of anti-delta and anti-Omicron spike receptor-binding domain (RBD) antibodies in a total of 78 cancer patients. In the analysis, they also included 25 healthcare workers as controls.

In response to vaccination, healthcare workers showed higher levels of total anti-spike antibodies compared to cancer patients. The lowest level of wildtype RBD-specific antibodies was observed in hematologic cancer patients receiving B cell-targeted treatment, followed by hematologic cancer patients not receiving B cell-targeted treatment and patients with solid tumors. A similar trend was observed for delta- and Omicron-specific spike RBD antibodies.

The serum samples collected from hematologic cancer patients without B cell-targeted treatment and solid tumor patients significantly inhibited the interaction between wildtype/delta RBD and angiotensin-converting enzyme 2 (ACE2; host cell receptor for viral entry). However, a significantly lower level of inhibition was observed for patients receiving B cell-targeted treatment. Importantly, a marked reduction in inhibition of Omicron RBD – ACE2 interaction was observed for all patients with solid tumors and hematologic cancer.

Study significance

The study demonstrates an increased incidence of vaccine breakthrough infections but a reduced disease severity among patients with solid tumors and hematologic cancer during the Omicron wave compared to the delta wave.

The study also highlights that COVID-19 vaccine-induced antibody response is lower in cancer patients than in healthy individuals. The reduction in antibody response is highest among hematologic patients receiving B cell-targeted treatment. Overall, a significant impairment in vaccine-induced Omicron neutralization has been observed in cancer patients.

Journal reference:
Mair, M. et al. (2022) “Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron”, Cancer Cell. doi: 10.1016/j.ccell.2022.04.003. https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00165-9

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