7CAM

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

PDB DOI: https://doi.org/10.2210/pdb7CAM/pdb

Classification: VIRAL PROTEIN
Organism(s): Severe acute respiratory syndrome coronavirus 2
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2020-06-09 Released: 2021-05-05
Deposition Author(s): Wang, Y.C., Yang, C.S., Hou, M.H., Tsai, C.L., Chou, Y.Z., Chen, Y.
Funding Organization(s): Ministry of Science and Technology (MoST, Taiwan)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.85 Å
R-Value Free: 0.309
R-Value Work: 0.201
R-Value Observed: 0.212

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

This is version 1.1 of the entry. See complete history.

Literature

Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug.

Wang, Y.C., Yang, W.H., Yang, C.S., Hou, M.H., Tsai, C.L., Chou, Y.Z., Hung, M.C., Chen, Y.

(2020) Am J Cancer Res 10: 2535-2545

PubMed: 32905393 Search on PubMedSearch on PubMed Central
Primary Citation of Related Structures:
7CAM, 7CB7

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 ^pro) 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 ^pro is similar to target therapy to treat cancer. Previous studies show that GC376, a broad-spectrum dipeptidyl M ^pro 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 ₅₀ value of M ^pro 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 ^pro tightly (K _D = 1.6 μM) and efficiently inhibit its proteolytic activity (IC ₅₀ = 0.89 μM). We also elucidate the high-resolution structure of dimeric SARS-CoV-2 M ^pro in complex with GC376. The cocrystal structure showed that GC376 and the catalytic Cys145 of M ^pro 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.

Organizational Affiliation

Institute of New Drug Development, China Medical University Taichung 40402, Taiwan.

Macromolecule Content

Total Structure Weight: 67.77 kDa
Atom Count: 4,706
Modelled Residue Count: 595
Deposited Residue Count: 614
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
3C-like proteinase	A, B	307	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0 EC: 3.4.22.69
UniProt
Find proteins for P0DTD1 (Severe acute respiratory syndrome coronavirus 2) Explore P0DTD1 Go to UniProtKB: P0DTD1
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P0DTD1
Sequence Annotations Expand
Reference Sequence