7B3E

Crystal structure of myricetin covalently bound to the main protease (3CLpro/Mpro) of SARS-CoV-2

PDB DOI: https://doi.org/10.2210/pdb7B3E/pdb

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

Deposited: 2020-11-30 Released: 2021-01-13
Deposition Author(s): Costanzi, E., Demitri, N., Giabbai, B., Storici, P.
Funding Organization(s): European Commission

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.77 ?
R-Value Free: 0.204
R-Value Work: 0.171
R-Value Observed: 0.173

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen.

Kuzikov, M., Costanzi, E., Reinshagen, J., Esposito, F., Vangeel, L., Wolf, M., Ellinger, B., Claussen, C., Geisslinger, G., Corona, A., Iaconis, D., Talarico, C., Manelfi, C., Cannalire, R., Rossetti, G., Gossen, J., Albani, S., Musiani, F., Herzog, K., Ye, Y., Giabbai, B., Demitri, N., Jochmans, D., Jonghe, S., Rymenants, J., Summa, V., Tramontano, E., Beccari, A.R., Leyssen, P., Storici, P., Neyts, J., Gribbon, P., Zaliani, A.

(2021) Acs Pharmacol Transl Sci 4: 1096-1110

PubMed: 35287429 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsptsci.0c00216
Primary Citation of Related Structures:
7B3E

PubMed Abstract:
Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC ₅₀ values below 1 μM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 ?, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

Organizational Affiliation

Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, 22525 Hamburg, Germany.

Macromolecule Content

Total Structure Weight: 68.97 kDa
Atom Count: 5,190
Modelled Residue Count: 602
Deposited Residue Count: 612
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Main Protease	A, B	306	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0 Gene Names: rep, 1a-1b EC: 3.4.19.12 (PDB Primary Data), 3.4.22 (PDB Primary Data), 3.4.22.69 (PDB Primary Data), 2.7.7.48 (PDB Primary Data), 3.6.4.12 (PDB Primary Data), 3.6.4.13 (PDB Primary Data), 3.1.13 (PDB Primary Data), 3.1 (PDB Primary Data), 2.1.1 (PDB Primary Data)
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

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
MYC (Subject of Investigation/LOI) Query on MYC Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain O [auth B] MOL2 format, chain I [auth A] MOL2 format, chain O [auth B] mmCIF format, chain I [auth A] mmCIF format, chain O [auth B]	I [auth A], O [auth B]	3,5,7-TRIHYDROXY-2-(3,4,5-TRIHYDROXYPHENYL)-4H-CHROMEN-4-ONE C₁₅ H₁₀ O₈ IKMDFBPHZNJCSN-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain O [auth B] Interactions & Density Focus chain I [auth A] Focus chain O [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain J [auth B] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain N [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B]	C [auth A] D [auth A] E [auth A] F [auth A] G [auth A] C [auth A], D [auth A], E [auth A], F [auth A], G [auth A], J [auth B], K [auth B], L [auth B], M [auth B], N [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain H [auth A] MOL2 format, chain H [auth A] mmCIF format, chain H [auth A]	H [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain H [auth A] Interactions & Density Focus chain H [auth A]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain P [auth B] MOL2 format, chain P [auth B] mmCIF format, chain P [auth B]	P [auth B]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain P [auth B] Interactions & Density Focus chain P [auth B]