scholarly journals Determination of intermediate state structures in the opening pathway of SARS-CoV-2 spike using cryo-electron microscopy

2021 ◽  
Author(s):  
Z. Faidon Brotzakis ◽  
Thomas Lohr ◽  
Michele Vendruscolo
Keyword(s):  
Infectious Disease ◽  
Electron Microscopy ◽  
Severe Acute Respiratory Syndrome ◽  
Intermediate State ◽  
Therapeutic Interventions ◽  
Cryo Electron Microscopy ◽  
Welfare Systems

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a highly infectious disease that is severely affecting our society and welfare systems. In order to develop therapeutic interventions against this...

scholarly journals Determination of Intermediate State Structures in the Opening Pathway of SARS-CoV-2 Spike Using Cryo-Electron Microscopy

2020 ◽  
Author(s):  
Zacharias Faidon Brotzakis ◽  
Thomas Lohr ◽  
Michele Vendruscolo
Keyword(s):  
Electron Microscopy ◽  
Host Cells ◽  
Therapeutic Interventions ◽  
Transmembrane Glycoprotein ◽  
Cryo Electron Microscopy ◽  
Welfare Systems ◽  
Intermediate States ◽  
Repurposed Drugs ◽  
Cryptic Binding Sites

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID19, a highly infectious disease that is severely affecting our society and welfare systems. In order to develop therapeutic interventions against this condition, one promising strategy is to target spike, the trimeric transmembrane glycoprotein that the virus uses to recognise and bind its host cells. Here we use a metainference cryo-electron microscopy approach to determine the opening pathway that brings spike from its inactive (closed) conformation to its active (open) one. The knowledge of the structures of the intermediate states of spike along these opening pathways enables us to identify a cryptic pocket that is not exposed in the open and closed states. We then identify compounds that bind the cryptic pocket by screening a library of repurposed drugs. These results underline the opportunities offered by the determination of the structures of the intermediate states populated during the dynamics of proteins to allow the therapeutic targeting of otherwise invisible cryptic binding sites.

scholarly journals Determination of Intermediate State Structures in the Opening Pathway of SARS-CoV-2 Spike Using Cryo-Electron Microscopy

2020 ◽  
Author(s):  
Zacharias Faidon Brotzakis ◽  
Thomas Lohr ◽  
Michele Vendruscolo
Keyword(s):  
Electron Microscopy ◽  
Host Cells ◽  
Therapeutic Interventions ◽  
Transmembrane Glycoprotein ◽  
Cryo Electron Microscopy ◽  
Welfare Systems ◽  
Intermediate States ◽  
Repurposed Drugs ◽  
Cryptic Binding Sites

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID19, a highly infectious disease that is severely affecting our society and welfare systems. In order to develop therapeutic interventions against this condition, one promising strategy is to target spike, the trimeric transmembrane glycoprotein that the virus uses to recognise and bind its host cells. Here we use a metainference cryo-electron microscopy approach to determine the opening pathway that brings spike from its inactive (closed) conformation to its active (open) one. The knowledge of the structures of the intermediate states of spike along these opening pathways enables us to identify a cryptic pocket that is not exposed in the open and closed states. We then identify compounds that bind the cryptic pocket by screening a library of repurposed drugs. These results underline the opportunities offered by the determination of the structures of the intermediate states populated during the dynamics of proteins to allow the therapeutic targeting of otherwise invisible cryptic binding sites.

scholarly journals The glycosylation in SARS-CoV-2 and its receptor ACE2

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yanqiu Gong ◽  
Suideng Qin ◽  
Lunzhi Dai ◽  
Zhixin Tian
Keyword(s):  
Infectious Disease ◽  
Electron Microscopy ◽  
Severe Acute Respiratory Syndrome ◽  
Host Recognition ◽  
Biological Functions ◽  
Cryo Electron Microscopy ◽  
And Topology ◽  
Human Receptor ◽  
Glycosylated Proteins

AbstractCoronavirus disease 2019 (COVID-19), a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 235 million individuals and led to more than 4.8 million deaths worldwide as of October 5 2021. Cryo-electron microscopy and topology show that the SARS-CoV-2 genome encodes lots of highly glycosylated proteins, such as spike (S), envelope (E), membrane (M), and ORF3a proteins, which are responsible for host recognition, penetration, binding, recycling and pathogenesis. Here we reviewed the detections, substrates, biological functions of the glycosylation in SARS-CoV-2 proteins as well as the human receptor ACE2, and also summarized the approved and undergoing SARS-CoV-2 therapeutics associated with glycosylation. This review may not only broad the understanding of viral glycobiology, but also provide key clues for the development of new preventive and therapeutic methodologies against SARS-CoV-2 and its variants.

Enhanced information from biological materials through technological improvements in cryo-electron microscopy

1992 ◽  
Vol 50 (1) ◽  
pp. 788-789
Author(s):  
Marc J.C. de Jong ◽  
Wim M. Busing ◽  
Max T. Otten
Keyword(s):  
Electron Microscopy ◽  
Electron Beam ◽  
Biological Materials ◽  
Electron Crystallography ◽  
Cryo Electron Microscopy ◽  
Transmission Electron ◽  
The Many ◽  
Technological Improvements ◽  
Beam Damage

Biological materials damage rapidly in the electron beam, limiting the amount of information that can be obtained in the transmission electron microscope. The discovery that observation at cryo temperatures strongly reduces beam damage (in addition to making it unnecessaiy to use chemical fixatives, dehydration agents and stains, which introduce artefacts) has given an important step forward to preserving the ‘live’ situation and makes it possible to study the relation between function, chemical composition and morphology.Among the many cryo-applications, the most challenging is perhaps the determination of the atomic structure. Henderson and co-workers were able to determine the structure of the purple membrane by electron crystallography, providing an understanding of the membrane's working as a proton pump. As far as understood at present, the main stumbling block in achieving high resolution appears to be a random movement of atoms or molecules in the specimen within a fraction of a second after exposure to the electron beam, which destroys the highest-resolution detail sought.

scholarly journals Synthetic self-assembling ADDomer platform for highly efficient vaccination by genetically encoded multiepitope display

2019 ◽  
Vol 5 (9) ◽  
pp. eaaw2853 ◽  
Author(s):  
Charles Vragniau ◽  
Joshua C. Bufton ◽  
Frédéric Garzoni ◽  
Emilie Stermann ◽  
Fruzsina Rabi ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Electron Microscopy ◽  
High Performance ◽  
Vaccine Candidate ◽  
Cost Effective ◽  
Atomic Resolution ◽  
Self Assembling ◽  
Cryo Electron Microscopy ◽  
Architectural Features ◽  
Multimeric Protein

Self-assembling virus-like particles represent highly attractive tools for developing next-generation vaccines and protein therapeutics. We created ADDomer, an adenovirus-derived multimeric protein-based self-assembling nanoparticle scaffold engineered to facilitate plug-and-play display of multiple immunogenic epitopes from pathogens. We used cryo–electron microscopy at near-atomic resolution and implemented novel, cost-effective, high-performance cloud computing to reveal architectural features in unprecedented detail. We analyzed ADDomer interaction with components of the immune system and developed a promising first-in-kind ADDomer-based vaccine candidate to combat emerging Chikungunya infectious disease, exemplifying the potential of our approach.

scholarly journals Advances in Structure Modeling Methods for Cryo-Electron Microscopy Maps

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 82 ◽  
Author(s):  
Eman Alnabati ◽  
Daisuke Kihara
Keyword(s):  
Electron Microscopy ◽  
De Novo ◽  
Molecular Structures ◽  
Structure Modeling ◽  
Rapid Progress ◽  
Macromolecular Complexes ◽  
Modeling Methods ◽  
Cryo Electron Microscopy ◽  
Density Maps

Cryo-electron microscopy (cryo-EM) has now become a widely used technique for structure determination of macromolecular complexes. For modeling molecular structures from density maps of different resolutions, many algorithms have been developed. These algorithms can be categorized into rigid fitting, flexible fitting, and de novo modeling methods. It is also observed that machine learning (ML) techniques have been increasingly applied following the rapid progress of the ML field. Here, we review these different categories of macromolecule structure modeling methods and discuss their advances over time.

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