Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants

The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.

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Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization

10.1101/2022.01.10.475532 ◽

2022 ◽

Author(s):

Qin Hong ◽

Wenyu Han ◽

Jiawei Li ◽

Shiqi Xu ◽

Yifan Wang ◽

...

Keyword(s):

Surface Properties ◽

Immune Evasion ◽

Broad Spectrum ◽

Molecular Basis ◽

Structural Basis ◽

Salt Bridges ◽

High Importance ◽

Closed State ◽

Open States

The SARS-CoV-2 Omicron variant exhibits striking immune evasion and is spreading globally at an unprecedented speed. Understanding the underlying structural basis of the high transmissibility and greatly enhanced immune evasion of Omicron is of high importance. Here through cryo-EM analysis, we present both the closed and open states of the Omicron spike, which appear more compact than the counterparts of the G614 strain, potentially related to the Omicron substitution induced enhanced protomer-protomer and S1-S2 interactions. The closed state showing dominant population may indicate a conformational masking mechanism of immune evasion for Omicron spike. Moreover, we capture two states for the Omicron S/ACE2 complex with S binding one or two ACE2s, revealing that the substitutions on the Omicron RBM result in new salt bridges/H-bonds and more favorable electrostatic surface properties, together strengthened interaction with ACE2, in line with the higher ACE2 affinity of the Omicron relative to the G614 strain. Furthermore, we determine cryo-EM structures of the Omicron S/S3H3 Fab, an antibody able to cross-neutralize major variants of concern including Omicron, elucidating the structural basis for S3H3-mediated broad-spectrum neutralization. Our findings shed new lights on the high transmissibility and immune evasion of the Omicron variant and may also inform design of broadly effective vaccines against emerging variants.

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Structure of SARS-CoV-2 ORF8, a rapidly evolving coronavirus protein implicated in immune evasion

10.1101/2020.08.27.270637 ◽

2020 ◽

Cited By ~ 7

Author(s):

Thomas G. Flower ◽

Cosmo Z. Buffalo ◽

Richard M. Hooy ◽

Marc Allaire ◽

Xuefeng Ren ◽

...

Keyword(s):

Immune Responses ◽

Immune Evasion ◽

Immune Suppression ◽

Molecular Basis ◽

Large Scale ◽

Terminal Sequence ◽

Specific Sequence ◽

X Ray ◽

X Ray Crystallography ◽

Rapid Spread

AbstractThe molecular basis for the severity and rapid spread of the COVID-19 disease caused by SARS-CoV-2 is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04 Å resolution by x-ray crystallography. The structure reveals a ~60 residue core similar to SARS-CoV ORF7a with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate non-covalent interface is formed by another SARS-CoV-2-specific sequence, 73YIDI76. Together the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.

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Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2021785118 ◽

2020 ◽

Vol 118 (2) ◽

pp. e2021785118

Author(s):

Thomas G. Flower ◽

Cosmo Z. Buffalo ◽

Richard M. Hooy ◽

Marc Allaire ◽

Xuefeng Ren ◽

...

Keyword(s):

Immune Responses ◽

Immune Evasion ◽

Immune Suppression ◽

Molecular Basis ◽

Large Scale ◽

Terminal Sequence ◽

Specific Sequence ◽

X Ray ◽

X Ray Crystallography ◽

Rapid Spread

The molecular basis for the severity and rapid spread of the COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-Å resolution by X-ray crystallography. The structure reveals a ∼60-residue core similar to SARS-CoV-2 ORF7a, with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate noncovalent interface is formed by another SARS-CoV-2−specific sequence, 73YIDI76. Together, the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.

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Renilla Bioluminescence: A Morphologic Approach to the Location of Photocytes

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100051050 ◽

1974 ◽

Vol 32 ◽

pp. 208-209

Author(s):

Ben O. Spurlock ◽

Milton J. Cormier

Keyword(s):

Excited State ◽

Ground State ◽

Molecular Basis ◽

Light Emission ◽

Chemical Basis ◽

Electronic Excited State ◽

Colonial Form ◽

The Common ◽

Eighteenth And Nineteenth Centuries ◽

Catalyzed Oxidation

The phenomenon of bioluminescence has fascinated layman and scientist alike for many centuries. During the eighteenth and nineteenth centuries a number of observations were reported on the physiology of bioluminescence in Renilla, the common sea pansy. More recently biochemists have directed their attention to the molecular basis of luminosity in this colonial form. These studies have centered primarily on defining the chemical basis for bioluminescence and its control. It is now established that bioluminescence in Renilla arises due to the luciferase-catalyzed oxidation of luciferin. This results in the creation of a product (oxyluciferin) in an electronic excited state. The transition of oxyluciferin from its excited state to the ground state leads to light emission.

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Androgen-induced plasticity at a “vocal” neuromuscular synapse

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100167895 ◽

1994 ◽

Vol 52 ◽

pp. 32-33

Author(s):

Darcy B. Kelley ◽

Martha L. Tobias ◽

Mark Ellisman

Keyword(s):

Xenopus Laevis ◽

Motor Neurons ◽

Sexual Differentiation ◽

Molecular Basis ◽

Neuromuscular Synapse ◽

Sexually Dimorphic ◽

Intracellular Protein ◽

Developmental Program ◽

Androgen Action ◽

Clawed Frog

Brain and muscle are sexually differentiated tissues in which masculinization is controlled by the secretion of androgens from the testes. Sensitivity to androgen is conferred by the expression of an intracellular protein, the androgen receptor. A central problem of sexual differentiation is thus to understand the cellular and molecular basis of androgen action. We do not understand how hormone occupancy of a receptor translates into an alteration in the developmental program of the target cell. Our studies on sexual differentiation of brain and muscle in Xenopus laevis are designed to explore the molecular basis of androgen induced sexual differentiation by examining how this hormone controls the masculinization of brain and muscle targets.Our approach to this problem has focused on a highly androgen sensitive, sexually dimorphic neuromuscular system: laryngeal muscles and motor neurons of the clawed frog, Xenopus laevis. We have been studying sex differences at a synapse, the laryngeal neuromuscular junction, which mediates sexually dimorphic vocal behavior in Xenopus laevis frogs.

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