9VUW

Crystal structure of SARS-CoV-2 main protease with a deletion of Asn51

Summary for 9VUW

• Entry DOI: 10.2210/pdb9vuw/pdb
• Descriptor: 3C-like proteinase nsp5 (2 entities in total)
• Functional Keywords: severe acute respiratory syndrome coronavirus 2, main protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 33681.39

Authors

Zeng, R.,Lei, J. (deposition date: 2025-07-14, release date: 2026-02-18, Last modification date: 2026-03-18)

Primary citation

Zeng, R.,Cui, S.,Xia, X.,Huang, C.,Sun, J.,Deng, X.,Gui, Q.,Fan, H.,Liu, X.,Yu, Y.,Yang, S.,Lei, J.
An intrinsic loop-mediated structural stability modulating inhibitor potency in the SADS-CoV and SARS-CoV-2 main proteases.
Plos Pathog., 22:e1013981-e1013981, 2026

PubMed Abstract: Swine acute diarrhea syndrome coronavirus (SADS-CoV) poses a significant zoonotic risk. The absence of the structure of SADS-CoV main protease (Mpro) severely impedes the development of effective antiviral therapeutics. Here, we present the high-resolution structures of SADS-CoV Mpro and its complexes with inhibitors 27h and SY110, respectively. These two compounds inhibit SADS-CoV Mpro through a novel inhibition mechanism. Residues 40-53 of SADS-CoV Mpro adopt a single-helix conformation, in contrast to a coiled coil formed by two consecutive alpha-helices observed in SARS-CoV-2 Mpro. These structural differences contribute to the varying inhibitor potency between Alphacoronavirus (α-CoV) and Betacoronavirus (β-CoV) Mpros. We subsequently demonstrate that the absence of residue '51' in α-CoV Mpros plays a key role in these conformational changes. Furthermore, 27h was proved to efficiently suppress SADS-CoV replication in both cell-based assays and porcine intestinal organoids-marking the first such assessment. Overall, these findings reveal that intrinsic Mpro dynamics influence inhibitor potency and provide insights for designing broad-spectrum Mpro inhibitors.

PubMed: 41734227
DOI: 10.1371/journal.ppat.1013981

Experimental method

X-RAY DIFFRACTION (1.6 Å)