8JCM

The crystal structure of SARS-CoV-2 main protease in complex with Compound 55

Summary for 8JCM

• Entry DOI: 10.2210/pdb8jcm/pdb
• Descriptor: 3C-like proteinase nsp5, methyl (2S)-2-[(3-ethanoylphenyl)carbonylamino]-3-phenyl-propanoate, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: sars-cov-2, main protease, 3clpro, mpro, viral protease, compound 55, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34419.38

Authors

Zhao, Y.,Zhu, Y.,Rao, Z. (deposition date: 2023-05-11, release date: 2024-05-15, Last modification date: 2025-05-28)

Primary citation

Zhu, Y.,Meng, J.,Feng, B.,Zhao, Y.,Zang, Y.,Lu, L.,Su, M.,Yang, Q.,Zhang, Q.,Feng, L.,Zhao, J.,Shao, M.,Ma, Y.,Yang, X.,Yang, H.,Li, J.,Jiang, X.,Rao, Z.
De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes.
Structure, 32:1327-1334.e3, 2024

PubMed Abstract: The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (M) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Min vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens.

PubMed: 38925121
DOI: 10.1016/j.str.2024.05.019

Experimental method

X-RAY DIFFRACTION (1.61 Å)