2Q6G

Crystal structure of SARS-CoV main protease H41A mutant in complex with an N-terminal substrate

Summary for 2Q6G

• Entry DOI: 10.2210/pdb2q6g/pdb
• Related: 2Q6D 2Q6F
• Descriptor: severe acute respiratory syndrome coronavirus (SARS-CoV), Polypeptide chain (3 entities in total)
• Functional Keywords: coronavirus; sars-cov; main protease; 3c-like proteinase;substrate, hydrolase
• Biological source: SARS coronavirus; More
• Cellular location: Non-structural protein 3: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 4: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 6: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 7: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 8: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 9: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 10: Host cytoplasm, host perinuclear region (By similarity). Helicase: Host endoplasmic reticulum-Golgi intermediate compartment (Potential). Uridylate-specific endoribonuclease: Host cytoplasm, host perinuclear region (By similarity): P59641
• Total number of polymer chains: 4
• Total formula weight: 70009.87

Authors

Xue, X.Y.,Yang, H.T.,Xue, F.,Bartlam, M.,Rao, Z.H. (deposition date: 2007-06-05, release date: 2008-02-12, Last modification date: 2023-08-30)

Primary citation

Xue, X.,Yu, H.,Yang, H.,Xue, F.,Wu, Z.,Shen, W.,Li, J.,Zhou, Z.,Ding, Y.,Zhao, Q.,Zhang, X.C.,Liao, M.,Bartlam, M.,Rao, Z.
Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design.
J.Virol., 82:2515-2527, 2008

PubMed Abstract: Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M(pro)), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M(pro) and a severe acute respiratory syndrome CoV (SARS-CoV) M(pro) mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M(pro). A monomeric form of IBV M(pro) was identified for the first time in CoV M(pro) structures. A comparison of these two structures to other available M(pro) structures provides new insights for the design of substrate-based inhibitors targeting CoV M(pro)s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M(pro) and was found to demonstrate in vitro inactivation of IBV M(pro) and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M(pro).

PubMed: 18094151
DOI: 10.1128/JVI.02114-07

Experimental method

X-RAY DIFFRACTION (2.5 Å)