7NT4

X-ray structure of SCoV2-PLpro in complex with small molecule inhibitor

PDB DOI: https://doi.org/10.2210/pdb7NT4/pdb

Classification: HYDROLASE
Organism(s): Severe acute respiratory syndrome coronavirus 2
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2021-03-09 Released: 2022-02-02
Deposition Author(s): Napolitano, V., Mourao, A., Bostock, M., Matsuda, A., Czarna, A., Popowicz, G.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.68 ?
R-Value Free: 0.264
R-Value Work: 0.193
R-Value Observed: 0.197

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses.

Napolitano, V., Dabrowska, A., Schorpp, K., Mourao, A., Barreto-Duran, E., Benedyk, M., Botwina, P., Brandner, S., Bostock, M., Chykunova, Y., Czarna, A., Dubin, G., Frohlich, T., Holscher, M., Jedrysik, M., Matsuda, A., Owczarek, K., Pachota, M., Plettenburg, O., Potempa, J., Rothenaigner, I., Schlauderer, F., Slysz, K., Szczepanski, A., Greve-Isdahl Mohn, K., Blomberg, B., Sattler, M., Hadian, K., Popowicz, G.M., Pyrc, K.

(2022) Cell Chem Biol 29: 774

PubMed: 35021060 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1016/j.chembiol.2021.11.006
Primary Citation of Related Structures:
7NT4

PubMed Abstract:
The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PL ^pro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PL ^pro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in?vivo in mice and ex?vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

Organizational Affiliation

Helmholtz Zentrum München, Ingolst?dter Landstrasse 1, 85764 Neuherberg, Germany.

Macromolecule Content

Total Structure Weight: 74.16 kDa
Atom Count: 5,184
Modelled Residue Count: 621
Deposited Residue Count: 636
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Non-structural protein 3	A, B	318	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)
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
PRL (Subject of Investigation/LOI) Query on PRL 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 M [auth B] SDF format, chain N [auth B] SDF format, chain O [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B]	C [auth A] D [auth A] E [auth A] M [auth B] N [auth B] C [auth A], D [auth A], E [auth A], M [auth B], N [auth B], O [auth B]	PROFLAVIN C₁₃ H₁₁ N₃ WDVSHHCDHLJJJR-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain T [auth B] SDF format, chain U [auth B] SDF format, chain V [auth B] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] MOL2 format, chain V [auth B] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B] mmCIF format, chain V [auth B]	K [auth A], L [auth A], T [auth B], U [auth B], V [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain K [auth A] Focus chain L [auth A] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B] Interactions & Density Focus chain K [auth A] Focus chain L [auth A] Focus chain T [auth B] Focus chain U [auth B] Focus chain V [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain S [auth B] MOL2 format, chain J [auth A] MOL2 format, chain S [auth B] mmCIF format, chain J [auth A] mmCIF format, chain S [auth B]	J [auth A], S [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain S [auth B] Interactions & Density Focus chain J [auth A] Focus chain S [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B]	F [auth A] G [auth A] H [auth A] I [auth A] P [auth B] F [auth A], G [auth A], H [auth A], I [auth A], P [auth B], Q [auth B], R [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B]