9CGV
SARS-CoV-2 nsp12 NiRAN domain bound to a covalent inhibitor SW090466-1
This is a non-PDB format compatible entry.
Summary for 9CGV
| Entry DOI | 10.2210/pdb9cgv/pdb |
| EMDB information | 45587 |
| Descriptor | RNA-directed RNA polymerase nsp12, Non-structural protein 8, Non-structural protein 7, ... (9 entities in total) |
| Functional Keywords | complex, covalent, inhibitor, sars-cov-2, polymerase, niran, viral protein-rna-inhibitor complex, viral protein/rna/inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 More |
| Total number of polymer chains | 6 |
| Total formula weight | 191014.05 |
| Authors | Osinski, A.,Hernandez, G.,Tagliabracci, V.S. (deposition date: 2024-07-01, release date: 2025-03-12, Last modification date: 2025-04-23) |
| Primary citation | Hernandez, G.,Osinski, A.,Majumdar, A.,Eitson, J.L.,Antczak, M.,Pawlowski, K.,Niederstrasser, H.,Servage, K.A.,Posner, B.,Schoggins, J.W.,Ready, J.M.,Tagliabracci, V.S. Covalent inhibition of the SARS-CoV-2 NiRAN domain via an active-site cysteine. J.Biol.Chem., 301:108378-108378, 2025 Cited by PubMed Abstract: The kinase-like nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domain of nsp12 in SARS-CoV-2 catalyzes the formation of the 5' RNA cap structure. This activity is required for viral replication, offering a new target for the development of antivirals. Here, we develop a high-throughput assay to screen for small molecule inhibitors targeting the SARS-CoV-2 NiRAN domain. We identified NiRAN covalent inhibitor 2 (NCI-2), a compound with a reactive chloromethyl group that covalently binds to an active site cysteine (Cys53) in the NiRAN domain, inhibiting its activity. NCI-2 can enter cells, bind to, and inactivate ectopically expressed nsp12. A cryo-EM reconstruction of the SARS-CoV-2 replication-transcription complex bound to NCI-2 offers a detailed structural blueprint for rational drug design. Although NCI-2 showed limited potency against SARS-CoV-2 replication in cells, our work lays the groundwork for developing more potent and selective inhibitors targeting the NiRAN domain. This approach presents a promising therapeutic strategy for effectively combating COVID-19 and potentially mitigating future coronavirus outbreaks. PubMed: 40049411DOI: 10.1016/j.jbc.2025.108378 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.7 Å) |
Structure validation
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