The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor

https://doi.org/10.1016/j.bbrc.2019.02.105Get rights and content

Highlights

  • The crystal structure of MHV-A59 Mpro in complex with an inhibitor was determined.

  • The Michael acceptor N3 was found to be an irreversible inhibitor targeting the substrate binding pocket of MHV-A59 Mpro.

  • The complex structure revealed the crucial residues for inhibitor recognition.

Abstract

Mouse hepatitis virus A59 (MHV-A59) is a representative member of the genus betacoronavirus within the subfamily Coronavirinae, which infects the liver, brain and respiratory tract. Through different inoculation routes, MHV-A59 can provide animal models for encephalitis, hepatitis and pneumonia to explore viral life machinery and virus-host interactions. In viral replication, non-structural protein 5 (Nsp5), also termed main protease (Mpro), plays a dominant role in processing coronavirus-encoded polyproteins and is thus recognized as an ideal target of anti-coronavirus agents. However, no structure of the MHV-A59 Mpro has been reported, and molecular exploration of the catalysis mechanism remains hindered. Here, we solved the crystal structure of the MHV-A59 Mpro complexed with a Michael acceptor-based inhibitor, N3. Structural analysis revealed that the Cβ of the vinyl group of N3 covalently bound to C145 of the catalytic dyad of Mpro, which irreversibly inactivated cysteine protease activity. The lactam ring of the P1 side chain and the isobutyl group of the P2 side chain, which mimic the conserved residues at the same positions of the substrate, fit well into the S1 and S2 pockets. Through a comparative study with Mpro of other coronaviruses, we observed that the substrate-recognition pocket and enzyme inhibitory mechanism is highly conservative. Altogether, our study provided structural features of MHV-A59 Mpro and indicated that a Michael acceptor inhibitor is an ideal scaffold for antiviral drugs.

Keywords

Mouse hepatitis virus A59
Crystal structure
Main protease
N3

Cited by (0)

1

These authors contributed equally to this work.

View Abstract