8RV7

SARS-CoV-2 nsp16-nsp10 in complex with SAM derivative inhibitor 4

This is a non-PDB format compatible entry.

Summary for 8RV7

• Entry DOI: 10.2210/pdb8rv7/pdb
• Descriptor: 2'-O-methyltransferase nsp16, Non-structural protein 10, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (6 entities in total)
• Functional Keywords: nsp16, nsp10, 2'-o-methyltransferase, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 49579.46

Authors

Kalnins, G. (deposition date: 2024-01-31, release date: 2024-02-14, Last modification date: 2024-10-02)

Primary citation

Kalnins, G.,Rudusa, L.,Bula, A.,Zelencova-Gopejenko, D.,Bobileva, O.,Sisovs, M.,Tars, K.,Jirgensons, A.,Jaudzems, K.,Bobrovs, R.
Structural basis for inhibition of the SARS-CoV-2 nsp16 by substrate-based dual site inhibitors.
Chemmedchem, :e202400618-e202400618, 2024

PubMed Abstract: Coronaviruses, including SARS-CoV-2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16-nsp10 methylates the 2'-O- of subsequent nucleotides of viral mRNA. The 2'-O-methylation performed by nsp16-nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X-ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16-nsp10. We obtained eleven 3D crystal structures of the nsp16-nsp10 complexes with SAM-derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual-site targeting of both SAM and RNA sites correlates with higher inhibitory potential.

PubMed: 39258386
DOI: 10.1002/cmdc.202400618

Experimental method

X-RAY DIFFRACTION (1.9 Å)