7D7K

The crystal structure of SARS-CoV-2 papain-like protease in apo form

PDB DOI: https://doi.org/10.2210/pdb7D7K/pdb

Classification: VIRAL PROTEIN
Organism(s): Severe acute respiratory syndrome coronavirus 2
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2020-10-04 Released: 2021-04-21
Deposition Author(s): Zhao, Y., Sun, L., Yang, H.T., Rao, Z.H.
Funding Organization(s): National Natural Science Foundation of China (NSFC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.90 ?
R-Value Free: 0.207
R-Value Work: 0.183
R-Value Observed: 0.183

wwPDB Validation 3D Report Full Report

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

Literature

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors.

Zhao, Y., Du, X., Duan, Y., Pan, X., Sun, Y., You, T., Han, L., Jin, Z., Shang, W., Yu, J., Guo, H., Liu, Q., Wu, Y., Peng, C., Wang, J., Zhu, C., Yang, X., Yang, K., Lei, Y., Guddat, L.W., Xu, W., Xiao, G., Sun, L., Zhang, L., Rao, Z., Yang, H.

(2021) Protein Cell 12: 877-888

PubMed: 33864621 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1007/s13238-021-00836-9
Primary Citation of Related Structures:
7D7K, 7D7L

PubMed Abstract:
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over?6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M ^pro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC ₅₀ values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC ₅₀ value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

Organizational Affiliation

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.

Macromolecule Content

Total Structure Weight: 72.35 kDa
Atom Count: 5,599
Modelled Residue Count: 624
Deposited Residue Count: 624
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Non-structural protein 3	A, B	312	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 1 Gene Names: rep, 1a-1b EC: 3.4.22
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
CFF Query on CFF Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain P [auth B] MOL2 format, chain D [auth A] MOL2 format, chain P [auth B] mmCIF format, chain D [auth A] mmCIF format, chain P [auth B]	D [auth A], P [auth B]	CAFFEINE C₈ H₁₀ N₄ O₂ RYYVLZVUVIJVGH-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain P [auth B] Interactions & Density Focus chain D [auth A] Focus chain P [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain V [auth B] SDF format, chain W [auth B] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain V [auth B] MOL2 format, chain W [auth B] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain V [auth B] mmCIF format, chain W [auth B]	L [auth A], M [auth A], N [auth A], V [auth B], W [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain V [auth B] Focus chain W [auth B] Interactions & Density Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain V [auth B] Focus chain W [auth B]
ZN (Subject of Investigation/LOI) Query on ZN Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain O [auth B] MOL2 format, chain C [auth A] MOL2 format, chain O [auth B] mmCIF format, chain C [auth A] mmCIF format, chain O [auth B]	C [auth A], O [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain O [auth B] Interactions & Density Focus chain C [auth A] Focus chain O [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain E [auth A] 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 J [auth A] SDF format, chain K [auth A] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] SDF format, chain X [auth B] MOL2 format, chain E [auth A] 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 J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] MOL2 format, chain X [auth B] mmCIF format, chain E [auth A] 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 J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain U [auth B] mmCIF format, chain X [auth B]	E [auth A] F [auth A] G [auth A] H [auth A] I [auth A] E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], Q [auth B], R [auth B], S [auth B], T [auth B], U [auth B], X [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain X [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Focus chain X [auth B]