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SARS-CoV-2 Spike Glycoprotein 6VXX

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The outbreak of a novel coronavirus (SARS-CoV-2) represents a pandemic threat that has been declared a public health emergency of international concern. The SARS-CoV-2 Spike Glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. The structure of SARS-CoV-2 Spike Glycoprotein 6VXX should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.

Biologic Model of SARS-CoV-2 Spike Glycoprotein 3D printed and colored-coded to denote functional domains (NTD blue, RBD green, SD1, light tan, SD2 red-orange-yellow, FP cyan, RRAR brown). SCIENCE recently published the work of Daniel Wrapp crystalizing the current generation of the SARS-CoV-2 Spike Glycoprotein, 2019-nCoV-2. Following the illustrations and supplemental materials describing each domain by amino acid sequence, a series of 3D models were generated for interactive exploration and 3D printing.

SCIENCE Image Gallery

Text and Illustrations from SCIENCE publication: “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.”

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SARS-CoV-2 Spike Glycoprotein

The membrane-bound configuration of SARS-CoV-2 Spike Glycoprotein (PDB ID: 6VXX seen below) is a trimer complex. Each monomer of the trimer is broken into two primary domains (S1 and S2) and then further characterized by a series of functional domains that facilitate either host identification and membrane fusion.

At the beginning of each S1 domain of the Spike Glycoprotein is the N-terminal Domain (Blue). It is associated with the stabilization of adjacent monomers of the Spike Glycoprotein. Following it is the Receptor-Binding Domain (RBD green) that binds angiotensin-converting enzyme 2 (ACE2) with a higher affinity than it does severe acute respiratory syndrome SARS-Coronavirus ‘Classic’ (2002). This in part is due to the unique RBD Binding Motif (dark green) that matches the binding motif of a similar Coronavirus found in Pangolins. Several published SARS-CoV-1 RBD-specific monoclonal antibodies were tested and found that they do not have appreciable binding to SARS-CoV-2, suggesting that antibody cross-reactivity may be limited, in part due to changes to these residues (Dark Green).

Spike protein S2 (residue 686-1273) mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. During viral and target cell membrane fusion, the coiled-coil regions (light yellow) assume a trimer-of-hairpins structure, positioning the Fusion Peptide (White) in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive the apposition and subsequent fusion of viral and target cell membranes.

3D Print SARS-CoV-2 Spike Glycoprotein 6VXX-6M17 (‘Down & Up’)

Model Description

Biologic Model of SARS-CoV-2 Glycoprotein Spike 6vxx 3D printed in Full-color Sandstone or Multi-colored Plastic and colored to match “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation” published recently in SCIENCE.

“The novel coronavirus 2019-nCoV has recently emerged as a human pathogen in the city of Wuhan in China’s Hubei province, causing fever, severe respiratory illness, and pneumonia—a disease recently named COVID-19 (12). The emerging pathogen was rapidly characterized as a new member of the betacoronavirus genus, closely related to several bat coronaviruses and to severe acute respiratory syndrome coronavirus (SARS-CoV) (34). Compared with SARS-CoV, 2019-nCoV appears to be more readily transmitted from human to human, spreading to multiple continents and leading to the WHO’s declaration of a Public Health Emergency of International Concern (PHEIC) on 30 January 2020 (156).”

“Up” and “Down” SARS CoV-2

“SARS-CoV-2 makes use of a densely glycosylated spike (S) protein to gain entry into host cells. The S protein is a trimeric class I fusion protein that exists in a metastable prefusion conformation that undergoes a substantial structural rearrangement to fuse the viral membrane with the host cell membrane (78). This process is triggered when the S1 subunit binds to a host cell receptor. Receptor binding destabilizes the prefusion trimer, resulting in shedding of the S1 subunit and transition of the S2 subunit to a stable postfusion conformation (9).”
3D Animated “Up-Down” Conformation Change

To engage a host cell receptor, the receptor-binding domain (RBD) of S1 undergoes hinge-like conformational movements that transiently hide or expose the determinants of receptor binding. These two states are referred to as the “down” conformation and the “up” conformation, where down corresponds to the receptor-inaccessible state and up corresponds to the receptor-accessible state, which is thought to be less stable (1013).

Biologic Explorer: 6VXX-6M17

To better understand the structural relationship of N-terminal (NTD) and Receptor Binding Domain (RBD) to Agiontensin-converting Enzyme 2 Receptor (ACE2), a theoretical model of SARS-CoV-2 Spike Glycoprotein was constructed from PDB ID: 6VXX and 6M17 after simulating the Spike Glycoprotein ‘Up-Down.’ conformation.