8RV6

SARS-CoV-2 nsp16-nsp10 in complex with SAM derivative inhibitor 2

PDB DOI: https://doi.org/10.2210/pdb8RV6/pdb

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

Deposited: 2024-01-31 Released: 2024-02-14
Deposition Author(s): Kalnins, G.
Funding Organization(s): Not funded

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.25 Å
R-Value Free: 0.225
R-Value Work: 0.195
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 1.1 of the entry. See complete history.

Literature

Structural basis for inhibition of the SARS-CoV-2 nsp16 by substrate-based dual site inhibitors.

Kalnins, G., Rudusa, L., Bula, A., Zelencova-Gopejenko, D., Bobileva, O., Sisovs, M., Tars, K., Jirgensons, A., Jaudzems, K., Bobrovs, R.

(2024) ChemMedChem : e202400618-e202400618

PubMed: 39258386 Search on PubMed
DOI: https://doi.org/10.1002/cmdc.202400618
Primary Citation of Related Structures:
8RV4, 8RV5, 8RV6, 8RV7, 8RV8, 8RV9, 8RVA, 8RVB, 8RZC, 8RZD, 8RZE

PubMed Abstract:
Coronaviruses, including SARS-CoV-2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM-dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16-nsp10 methylates the 2'-O- of subsequent nucleotides of viral mRNA. The 2'-O-methylation performed by nsp16-nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X-ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16-nsp10. We obtained eleven 3D crystal structures of the nsp16-nsp10 complexes with SAM-derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual-site targeting of both SAM and RNA sites correlates with higher inhibitory potential.

Organizational Affiliation

Latvian Biomedical Research and Study Centre, Structural Biology Group, LATVIA.

Macromolecule Content

Total Structure Weight: 49.89 kDa
Atom Count: 3,410
Modelled Residue Count: 413
Deposited Residue Count: 444
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
2'-O-methyltransferase nsp16	A	302	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0 Gene Names: rep, 1a-1b EC: 2.1.1.57
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

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Non-structural protein 10	B	142	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 0
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
A1H3B (Subject of Investigation/LOI) Query on A1H3B Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	3-[[(2~{S},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methylsulfanylmethyl]-5-(4-hydroxyphenyl)benzoic acid C₂₄ H₂₃ N₅ O₆ S PZWOIOSYCOECFR-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
MES Query on MES Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	2-(N-MORPHOLINO)-ETHANESULFONIC ACID C₆ H₁₃ N O₄ S SXGZJKUKBWWHRA-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain I [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain I [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain I [auth B]	E [auth A], F [auth A], I [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain I [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain I [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain G [auth B] SDF format, chain H [auth B] MOL2 format, chain G [auth B] MOL2 format, chain H [auth B] mmCIF format, chain G [auth B] mmCIF format, chain H [auth B]	G [auth B], H [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain G [auth B] Focus chain H [auth B] Interactions & Density Focus chain G [auth B] Focus chain H [auth B]