9S2V
NSP14 IN COMPLEX WITH LIGAND TDI-014925-CL-2 (compound 58)
This is a non-PDB format compatible entry.
Summary for 9S2V
| Entry DOI | 10.2210/pdb9s2v/pdb |
| Descriptor | Guanine-N7 methyltransferase nsp14, ZINC ION, S-ADENOSYL-L-HOMOCYSTEINE, ... (7 entities in total) |
| Functional Keywords | novel coronavirus, viral protein |
| Biological source | SARS-CoV-2 pseudovirus |
| Total number of polymer chains | 2 |
| Total formula weight | 122192.80 |
| Authors | Steinbacher, S.,Huggins, D.J. (deposition date: 2025-07-22, release date: 2025-09-17, Last modification date: 2025-10-08) |
| Primary citation | Miller, M.W.,Meyer, C.,Garzia, A.,Hoffmann, H.H.,Khan, T.A.,Egbertson, M.,Myers, R.W.,Liverton, N.,Kargman, S.,Davis, J.A.,Ganichkin, O.,Nitsche, J.,Steinbacher, S.,Dagan, S.,Glickman, J.F.,Rice, C.M.,Tuschl, T.,Meinke, P.T.,Huggins, D.J. Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors. J.Med.Chem., 68:19076-19106, 2025 Cited by PubMed Abstract: We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic. PubMed: 40910582DOI: 10.1021/acs.jmedchem.5c01155 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.38 Å) |
Structure validation
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