9HH6 | pdb_00009hh6

Crystal Structure of Nsp15 Endoribonuclease from SARS CoV-2 in Complex with TAS-103

PDB DOI: https://doi.org/10.2210/pdb9HH6/pdb

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

Deposited: 2024-11-21 Released: 2025-05-28
Deposition Author(s): Chatziefthymiou, S.D., Kolbe, M., Hakanpaeae, J., Labahn, J., Windshuegel, B.
Funding Organization(s): Other government

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 ?
R-Value Free:
0.177 (Depositor), 0.182 (DCC)
R-Value Work:
0.162 (Depositor), 0.169 (DCC)
R-Value Observed:
0.162 (Depositor)

Method: SOLUTION SCATTERING

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Identification, validation, and characterization of approved and investigational drugs interfering with the SARS-CoV-2 endoribonuclease Nsp15.

Chatziefthymiou, S.D., Kuzikov, M., Afandi, S., Kovacs, G., Srivastava, S., Zaliani, A., Gruzinov, A., Pompidor, G., Lunelli, M., Ahmed, G.R., Labahn, J., Hakanpaa, J., Windshugel, B., Kolbe, M.

(2025) Protein Sci 34: e70156-e70156

PubMed: 40371758 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/pro.70156
Primary Citation of Related Structures:
9HH5, 9HH6

PubMed Abstract:
Since the emergence of SARS-CoV-2 at the end of 2019, the virus has caused significant global health and economic disruptions. Despite the rapid development of antiviral vaccines and some approved treatments such as remdesivir and paxlovid, effective antiviral pharmacological treatments for COVID-19 patients remain limited. This study explores Nsp15, a 3'-uridylate-specific RNA endonuclease, which has a critical role in immune system evasion and hence in escaping the innate immune sensors. We conducted a comprehensive drug repurposing screen and identified 44 compounds that showed more than 55% inhibition of Nsp15 activity in a real-time fluorescence assay. A validation pipeline was employed to exclude unspecific interactions, and dose-response assays confirmed 29 compounds with an IC ₅₀ below 10?μM. Structural studies, including molecular docking and x-ray crystallography, revealed key interactions of identified inhibitors, such as TAS-103 and YM-155, with the Nsp15 active site and other critical regions. Our findings show that the identified compounds, particularly those retaining potency under different assay conditions, could serve as promising hits for developing Nsp15 inhibitors. Additionally, the study emphasizes the potential of combination therapies targeting multiple viral processes to enhance treatment efficacy and reduce the risk of drug resistance. This research contributes to the ongoing efforts to develop effective antiviral therapies for SARS-CoV-2 and possibly other coronaviruses.

Organizational Affiliation

Photon Science, DESY, Hamburg, Germany.

Macromolecule Content

Total Structure Weight: 78.98 kDa
Atom Count: 5,974
Modeled Residue Count: 692
Deposited Residue Count: 692
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
ORF1ab polyprotein	A	347	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0 Gene Names: ORF1ab
UniProt
Find proteins for A0A8B6RHF8 (Severe acute respiratory syndrome coronavirus 2) Explore A0A8B6RHF8 Go to UniProtKB: A0A8B6RHF8
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A0A8B6RHF8
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
ORF1ab polyprotein	B	345	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0 Gene Names: ORF1ab
UniProt
Find proteins for A0A8B1JY75 (Severe acute respiratory syndrome coronavirus 2) Explore A0A8B1JY75 Go to UniProtKB: A0A8B1JY75
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A0A8B1JY75
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1IUV (Subject of Investigation/LOI) Query on A1IUV Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain I [auth B] MOL2 format, chain C [auth A] MOL2 format, chain I [auth B] mmCIF format, chain C [auth A] mmCIF format, chain I [auth B]	C [auth A], I [auth B]	6-[2-(dimethylamino)ethylamino]-3-oxidanyl-indeno[2,1-c]quinolin-7-one C₂₀ H₁₉ N₃ O₂ ROWSTIYZUWEOMM-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain I [auth B] Interactions & Density Focus chain C [auth A] Focus chain I [auth B]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain J [auth B] MOL2 format, chain D [auth A] MOL2 format, chain J [auth B] mmCIF format, chain D [auth A] mmCIF format, chain J [auth B]	D [auth A], J [auth B]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain D [auth A] Focus chain J [auth B] Interactions & Density Focus chain D [auth A] Focus chain J [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 K [auth B] SDF format, chain L [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 K [auth B] MOL2 format, chain L [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 K [auth B] mmCIF format, chain L [auth B]	E [auth A] F [auth A] G [auth A] H [auth A] K [auth B] E [auth A], F [auth A], G [auth A], H [auth A], K [auth B], L [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 K [auth B] Focus chain L [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 K [auth B] Focus chain L [auth B]