8F4S
Crystal Structure of the SARS-CoV-2 2'-O-Methyltransferase with Compound 5a bound to the Cryptic Pocket of nsp16
Summary for 8F4S
| Entry DOI | 10.2210/pdb8f4s/pdb |
| Descriptor | 2'-O-methyltransferase, Non-structural protein 10, SODIUM ION, ... (7 entities in total) |
| Functional Keywords | csbid, center for structural biology of infectious diseases, methyl transferase, structural genomics, transferase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 More |
| Total number of polymer chains | 2 |
| Total formula weight | 49421.74 |
| Authors | Minasov, G.,Shuvalova, L.,Brunzelle, J.S.,Rosas-Lemus, M.,Kiryukhina, O.,Satchell, K.J.F.,Center for Structural Biology of Infectious Diseases (CSBID) (deposition date: 2022-11-11, release date: 2023-10-18, Last modification date: 2023-10-25) |
| Primary citation | Inniss, N.L.,Kozic, J.,Li, F.,Rosas-Lemus, M.,Minasov, G.,Rybacek, J.,Zhu, Y.,Pohl, R.,Shuvalova, L.,Rulisek, L.,Brunzelle, J.S.,Bednarova, L.,Stefek, M.,Kormanik, J.M.,Andris, E.,Sebestik, J.,Li, A.S.M.,Brown, P.J.,Schmitz, U.,Saikatendu, K.,Chang, E.,Nencka, R.,Vedadi, M.,Satchell, K.J.F. Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors. Acs Infect Dis., 9:1918-1931, 2023 Cited by PubMed Abstract: A collaborative, open-science team undertook discovery of novel small molecule inhibitors of the SARS-CoV-2 nsp16-nsp10 2'--methyltransferase using a high throughput screening approach with the potential to reveal new inhibition strategies. This screen yielded compound , a ligand possessing an electron-deficient double bond, as an inhibitor of SARS-CoV-2 nsp16 activity. Surprisingly, X-ray crystal structures revealed that covalently binds within a previously unrecognized cryptic pocket near the -adenosylmethionine binding cleft in a manner that prevents occupation by -adenosylmethionine. Using a multidisciplinary approach, we examined the mechanism of binding of compound to the nsp16 cryptic pocket and developed derivatives that inhibited nsp16 activity and murine hepatitis virus replication in rat lung epithelial cells but proved cytotoxic to cell lines canonically used to examine SARS-CoV-2 infection. Our study reveals the druggability of this newly discovered SARS-CoV-2 nsp16 cryptic pocket, provides novel tool compounds to explore the site, and suggests a new approach for discovery of nsp16 inhibition-based pan-coronavirus therapeutics through structure-guided drug design. PubMed: 37728236DOI: 10.1021/acsinfecdis.3c00203 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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