8IG6

Crystal structure of MERS main protease in complex with GC376

Summary for 8IG6

• Entry DOI: 10.2210/pdb8ig6/pdb
• Descriptor: ORF1a, N~2~-[(benzyloxy)carbonyl]-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Middle East respiratory syndrome-related coronavirus
• Total number of polymer chains: 2
• Total formula weight: 66802.41

Authors

Lin, C.,Zhang, J.,Li, J. (deposition date: 2023-02-20, release date: 2024-03-06, Last modification date: 2024-10-30)

Primary citation

Lin, C.,Zhu, Z.,Jiang, H.,Zou, X.,Zeng, X.,Wang, J.,Zeng, P.,Li, W.,Zhou, X.,Zhang, J.,Wang, Q.,Li, J.
Structural Basis for Coronaviral Main Proteases Inhibition by the 3CLpro Inhibitor GC376.
J.Mol.Biol., 436:168474-168474, 2024

PubMed Abstract: The main protease (M) of coronaviruses participates in viral replication, serving as a hot target for drug design. GC376 is able to effectively inhibit the activity of M, which is due to nucleophilic addition of GC376 by binding covalently with Cys145 in M active site. Here, we used fluorescence resonance energy transfer (FRET) assay to analyze the IC values of GC376 against Ms from six different coronaviruses (SARS-CoV-2, HCoV-229E, HCoV-HUK1, MERS-CoV, SARS-CoV, HCoV-NL63) and five M mutants (G15S, M49I, K90R, P132H, S46F) from SARS-CoV-2 variants. The results showed that GC376 displays effective inhibition to various coronaviral Ms and SARS-CoV-2 M mutants. In addition, the crystal structures of SARS-CoV-2 M (wide type)-GC376, SARS-CoV M-GC376, MERS-CoV M-GC376, and SARS-CoV-2 M mutants (G15S, M49I, S46F, K90R, and P132H)-GC376 complexes were solved. We found that GC376 is able to fit into the active site of Ms from different coronaviruses and different SARS-CoV-2 variants properly. Detailed structural analysis revealed key molecular determinants necessary for inhibition and illustrated the binding patterns of GC376 to these different Ms. In conclusion, we not only proved the inhibitory activity of GC376 against different Ms including SARS-CoV-2 M mutants, but also revealed the molecular mechanism of inhibition by GC376, which will provide scientific guidance for the development of broad-spectrum drugs against SARS-CoV-2 as well as other coronaviruses.

PubMed: 38311236
DOI: 10.1016/j.jmb.2024.168474

Experimental method

X-RAY DIFFRACTION (2.07 Å)