ISDA: 6XR3

Deposition Date 2020-07-10

Release Date 2020-08-19

Last Version Date 2026-04-22

Entry Detail

PDB ID:

6XR3

Keywords:

HYDROLASE

Title:

X-ray Structure of SARS-CoV-2 main protease bound to GRL-024-20 at 1.45 A

Biological Source:

Source Organism(s):

Severe acute respiratory syndrome coronavirus 2 (Taxon ID: 2697049)

Expression System(s):

Escherichia coli bl21(de3)

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

1.45 Å

R-Value Free:

0.18

R-Value Work:

0.14

R-Value Observed:

0.14

Space Group:

C 1 2 1

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Macromolecular Entities

Structures with similar UniProt ID

Protein Blast

Polymer Type:polypeptide(L)
Molecule:3C-like proteinase
Gene (Uniprot):rep
Chain IDs:A
Chain Length:306
Number of Molecules:1
Biological Source:Severe acute respiratory syndrome coronavirus 2

UniProt ID:P0DTD1 Pfam ID:PF05409 EC:2.7.7.48

Ligand Molecules

V7G

Primary Citation

A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication.

Hattori, S.I, Higashi-Kuwata, N, Hayashi, H, Allu, S.R, Raghavaiah, J, Bulut, H, Das, D, Anson, B.J, Lendy, E.K, Takamatsu, Y, Takamune, N, Kishimoto, N, Murayama, K, Hasegawa, K, Li, M, Davis, D.A, Kodama, E.N, Yarchoan, R, Wlodawer, A, Misumi, S, Mesecar, A.D, Ghosh, A.K, Mitsuya, H.Show

Nat Commun 12 668 668 (2021)

PMID: 33510133 DOI: 10.1038/s41467-021-20900-6

Abstact

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

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Primary Citation of related structures

Abstact

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