9Z0D | pdb_00009z0d

SARS-CoV-2 Papain-like Protease (PLpro) in complex with Fragment 41

PDB DOI: https://doi.org/10.2210/pdb9Z0D/pdb

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

Deposited: 2025-10-31 Released: 2026-02-18
Deposition Author(s): Taylor, A.J.
Funding Organization(s): National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.65 Å
R-Value Free:
0.238 (Depositor), 0.239 (DCC)
R-Value Work:
0.200 (Depositor), 0.201 (DCC)
R-Value Observed:
0.202 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

This is version 1.0 of the entry. See complete history.

Literature

Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.

Wei, Q., Taylor, A.J., Miriyala, N., Barmade, M.A., Gentry, Z.O., Anderson-Daniels, J., Teuscher, K.B., Crow, M.M., Apakama, C., South, T.M., Rietz, T.A., Amporndanai, K., Phan, J., Sensintaffar, J.L., Denison, M., Lee, T., Fesik, S.W.

(2026) J Med Chem

PubMed: 41629155 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.5c03704
Primary Citation of Related Structures:
9Z0C, 9Z0D

PubMed Abstract:
The papain-like protease (PL ^Pro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PL ^Pro led to the identification of a novel class of spiro[chromane-2,4'-piperidin]-4-one inhibitors exemplified by lead compound 7 . High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PL ^Pro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC ₅₀ = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC ₅₀ = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.

Organizational Affiliation

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.

Macromolecule Content

Total Structure Weight: 146.93 kDa
Atom Count: 11,285
Modeled Residue Count: 1,257
Deposited Residue Count: 1,276
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Papain-like protease nsp3	A, B, C, D	319	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 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1CZW (Subject of Investigation/LOI) Query on A1CZW Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth B] SDF format, chain J [auth C] SDF format, chain L [auth D] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B] MOL2 format, chain J [auth C] MOL2 format, chain L [auth D] mmCIF format, chain F [auth A] mmCIF format, chain H [auth B] mmCIF format, chain J [auth C] mmCIF format, chain L [auth D]	F [auth A], H [auth B], J [auth C], L [auth D]	N'-[3-(2-{[(7M)-8-methyl-7-(2-methylpyridin-4-yl)-3,4-dihydrospiro[[1]benzopyran-2,4'-piperidin]-1'-yl]methyl}pyridin-3-yl)propanoyl]-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-oxobutanehydrazide C₃₈ H₄₆ N₆ O₅ FOXKCTVUOUVVFM-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D] Interactions & Density Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth B] SDF format, chain I [auth C] SDF format, chain K [auth D] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain I [auth C] MOL2 format, chain K [auth D] mmCIF format, chain E [auth A] mmCIF format, chain G [auth B] mmCIF format, chain I [auth C] mmCIF format, chain K [auth D]	E [auth A], G [auth B], I [auth C], K [auth D]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D] Interactions & Density Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D]