7LYH

Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor UAWJ9-36-1

PDB DOI: https://doi.org/10.2210/pdb7LYH/pdb

Classification: VIRAL PROTEIN/INHIBITOR
Organism(s): Severe acute respiratory syndrome coronavirus 2
Expression System: Escherichia coli 'BL21-Gold(DE3)pLysS AG
Mutation(s): No

Deposited: 2021-03-07 Released: 2021-03-17
Deposition Author(s): Sacco, M., Wang, J., Chen, Y.
Funding Organization(s): National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.222
R-Value Work: 0.180
R-Value Observed: 0.182

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

Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir.

Xia, Z., Sacco, M., Hu, Y., Ma, C., Meng, X., Zhang, F., Szeto, T., Xiang, Y., Chen, Y., Wang, J.

(2021) Acs Pharmacol Transl Sci 4: 1408-1421

PubMed: 34414360 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsptsci.1c00099

PubMed Abstract:
SARS-CoV-2 main protease (M ^pro) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M ^pro is highly conserved among all seven human coronaviruses, with certain M ^pro inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 based on the superimposed X-ray crystal structures of SARS-CoV-2 M ^pro with GC-376, telaprevir, and boceprevir. Both UAWJ9-36-1 and UAWJ9-36-3 showed potent binding and enzymatic inhibition against the M ^pro's from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP M ^pro assay results show that UAWJ9-36-1 and UAWJ9-36-3 inhibited the intracellular protease activity of SARS-CoV-2 M ^pro. In addition, UAWJ9-36-1 and UAWJ9-36-3 had potent antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with UAWJ9-36-3 being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that UAWJ9-36-1 and UAWJ9-36-3 had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and cathepsin L, but not cathepsin K. The X-ray crystal structures of SARS-CoV-2 M ^pro with UAWJ9-36-1 and UAWJ9-36-3 were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 are promising candidates to be further developed as broad-spectrum coronavirus antivirals.

Organizational Affiliation

Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.

Macromolecule Content

Total Structure Weight: 34.44 kDa
Atom Count: 2,689
Modelled Residue Count: 304
Deposited Residue Count: 306
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
3C-like proteinase	A	306	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0 Gene Names: rep, 1a-1b 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

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
YHJ (Subject of Investigation/LOI) Query on YHJ Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	benzyl (1S,3aR,6aS)-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate C₂₃ H₃₁ N₃ O₅ BQHAUUUZCGWWEE-HVTWWXFQSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	C [auth A], D [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain C [auth A] Focus chain D [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.222
R-Value Work: 0.180
R-Value Observed: 0.182
Space Group: I 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 45.62	α = 90
b = 53.02	β = 100.71
c = 112.959	γ = 90

Software Package:

Software Name	Purpose
Aimless	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction
Aimless	data reduction
MOLREP	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2021-03-17

Deposition Author(s):

Sacco, M.

Wang, J.

Chen, Y.

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)	United States	AI147325
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)	United States	AI157046