7CAM

SARS-CoV-2 main protease (Mpro) apo structure (space group P212121)

Summary for 7CAM

• Entry DOI: 10.2210/pdb7cam/pdb
• Descriptor: 3C-like proteinase (2 entities in total)
• Functional Keywords: main protease, 3cl protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 67765.20

Authors

Wang, Y.C.,Yang, C.S.,Hou, M.H.,Tsai, C.L.,Chou, Y.Z.,Chen, Y. (deposition date: 2020-06-09, release date: 2021-05-05, Last modification date: 2023-11-29)

Primary citation

Wang, Y.C.,Yang, W.H.,Yang, C.S.,Hou, M.H.,Tsai, C.L.,Chou, Y.Z.,Hung, M.C.,Chen, Y.
Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug.
Am J Cancer Res, 10:2535-2545, 2020

PubMed Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV), took tens of thousands of lives and caused tremendous economic losses. The main protease (M) of SARS-CoV-2 is a potential target for treatment of COVID-19 due to its critical role in maturation of viral proteins and subsequent viral replication. Conceptually and technically, targeting therapy against M is similar to target therapy to treat cancer. Previous studies show that GC376, a broad-spectrum dipeptidyl M inhibitor, efficiently blocks the proliferation of many animal and human coronaviruses including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), porcine epidemic diarrhea virus (PEDV), and feline infectious peritonitis virus (FIPV). Due to the conservation of structure and catalytic mechanism of coronavirus main protease, repurposition of GC376 against SARS-CoV-2 may be an effective way for the treatment of COVID-19 in humans. To validate this conjecture, the binding affinity and IC value of M with GC376 was determined by isothermal titration calorimetry (ITC) and fluorescence resonance energy transfer (FRET) assay, respectively. The results showed that GC376 binds to SARS-CoV-2 M tightly (K = 1.6 μM) and efficiently inhibit its proteolytic activity (IC = 0.89 μM). We also elucidate the high-resolution structure of dimeric SARS-CoV-2 M in complex with GC376. The cocrystal structure showed that GC376 and the catalytic Cys145 of M covalently linked through forming a hemithioacetal group and releasing a sulfonic acid group. Because GC376 is already known as a broad-spectrum antiviral medication and successfully used in animal, it will be a suitable candidate for anti-COVID-19 treatment.

PubMed: 32905393

Experimental method

X-RAY DIFFRACTION (2.85 Å)