9FEH
Crystal structure of SARS-CoV-2 nsp14 methyltransferase domain in complex with the STM957 inhibitor
This is a non-PDB format compatible entry.
Summary for 9FEH
| Entry DOI | 10.2210/pdb9feh/pdb |
| Descriptor | Transcription factor ETV6,Guanine-N7 methyltransferase nsp14, ~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-[4-azanyl-5-(2-pyridin-3-ylethynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl]-3-cyano-~{N}-ethyl-4-methoxy-benzenesulfonamide, ZINC ION, ... (4 entities in total) |
| Functional Keywords | viral, sars-cov-2, covid-19, methyltransferase, rna cap, inhibitor, stm957, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 More |
| Total number of polymer chains | 1 |
| Total formula weight | 36181.45 |
| Authors | Zilecka, E.,Klima, M.,Boura, E. (deposition date: 2024-05-20, release date: 2024-08-28, Last modification date: 2024-09-04) |
| Primary citation | Zilecka, E.,Klima, M.,Stefek, M.,Dejmek, M.,Nencka, R.,Boura, E. Structure of SARS-CoV-2 MTase nsp14 with the inhibitor STM957 reveals inhibition mechanism that is shared with a poxviral MTase VP39. J Struct Biol X, 10:100109-100109, 2024 Cited by PubMed Abstract: Nsp14 is an RNA methyltransferase (MTase) encoded by all coronaviruses. In fact, many viral families, including DNA viruses, encode MTases that catalyze the methylation of the RNA precap structure, resulting in fully capped viral RNA. This capping is crucial for efficient viral RNA translation, stability, and immune evasion. Our previous research identified nsp14 inhibitors based on the chemical scaffold of its methyl donor - the S-adenosyl methionine (SAM) - featuring a modified adenine base and a substituted arylsulfonamide. However, the binding mode of these inhibitors was based only on docking experiments. To uncover atomic details of nsp14 inhibition we solved the crystal structure of nsp14 bound to STM957. The structure revealed the atomic details of nsp14 inhibition such that the 7-deaza-adenine moiety of STM957 forms specific interactions with Tyr368, Ala353, and Phe367, while the arylsulfonamide moiety engages with Asn388 and Phe506. The large aromatic substituent at the 7-deaza position displaces a network of water molecules near the adenine base. Surprisingly, this was recently observed in the case of an unrelated monkeypox MTase VP39, where the 7-deaza modified SAH analogs also displaced water molecules from the vicinity of the active site. PubMed: 39188530DOI: 10.1016/j.yjsbx.2024.100109 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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