With an alarm code, we can enter a building without bells going off. It turns out that the SARS coronavirus 2 (SARS-CoV-2) has the same advantage entering cells. It possesses the code to waltz right in.
In Nature Communications, researchers reported how the coronavirus achieves this. The scientists resolved the structure of an enzyme called nsp16, which the virus produces and then along with nsp10 modify viral messenger RNA cap to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction, said the study lead author.
"It's a camouflage," the author said. "Because of the modifications, which fool the cell, the resulting viral messenger RNA is now considered as part of the cell's own code and not foreign."
The authors report the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine (SAM). The nsp16/nsp10 heterodimer is captured in the act of 2′-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA.
The authors observe large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This induced fit model provides mechanistic insights into the 2′-O methylation of the viral mRNA cap. They also discover a distant (25 Å) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.
Deciphering the 3D structure of nsp16 paves the way for rational design of antiviral drugs for COVID-19 and other emerging coronavirus infections, the author said. The drugs, new small molecules, would inhibit nsp16 from making the modifications. The immune system would then pounce on the invading virus, recognizing it as foreign.
Camouflage by coronavirus to prevent detection!
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