9EPL

Mpro from SARS-CoV-2 with 298Q mutation

Summary for 9EPL

• Entry DOI: 10.2210/pdb9epl/pdb
• Descriptor: Non-structural protein 11, GLYCEROL, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: sars-cov-2, main protease, oligomerization, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 33546.10

Authors

Plewka, J.,Lis, K.,Czarna, A.,Pyrc, K.,Kantyka, T.,Chykunova, Y. (deposition date: 2024-03-18, release date: 2024-04-17, Last modification date: 2024-04-24)

Primary citation

Lis, K.,Plewka, J.,Menezes, F.,Bielecka, E.,Chykunova, Y.,Pustelny, K.,Niebling, S.,Garcia, A.S.,Garcia-Alai, M.,Popowicz, G.M.,Czarna, A.,Kantyka, T.,Pyrc, K.
SARS-CoV-2 M pro oligomerization as a potential target for therapy.
Int.J.Biol.Macromol., 267:131392-131392, 2024

PubMed Abstract: The main protease (M) of SARS-CoV-2 is critical in the virus's replication cycle, facilitating the maturation of polyproteins into functional units. Due to its conservation across taxa, M is a promising target for broad-spectrum antiviral drugs. Targeting M with small molecule inhibitors, such as nirmatrelvir combined with ritonavir (Paxlovid™), which the FDA has approved for post-exposure treatment and prophylaxis, can effectively interrupt the replication process of the virus. A key aspect of M's function is its ability to form a functional dimer. However, the mechanics of dimerization and its influence on proteolytic activity remain less understood. In this study, we utilized biochemical, structural, and molecular modelling approaches to explore M dimerization. We evaluated critical residues, specifically Arg4 and Arg298, that are essential for dimerization. Our results show that changes in the oligomerization state of M directly affect its enzymatic activity and dimerization propensity. We discovered a synergistic relationship influencing dimer formation, involving both intra- and intermolecular interactions. These findings highlight the potential for developing allosteric inhibitors targeting M, offering promising new directions for therapeutic strategies.

PubMed: 38582483
DOI: 10.1016/j.ijbiomac.2024.131392

Experimental method

X-RAY DIFFRACTION (1.8 Å)