8F4Y

Crystal Structure of SARS-CoV-2 2'-O-Methyltransferase in Complex with Compound 5a covalently bound to nsp16 and nsp10

Summary for 8F4Y

• Entry DOI: 10.2210/pdb8f4y/pdb
• Descriptor: 2'-O-methyltransferase, Non-structural protein 10, SODIUM ION, ... (8 entities in total)
• Functional Keywords: csbid, structural genomics, center for structural biology of infectious diseases, nsp16-10, 2'-o-methyltransferase, transferase
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 50686.23

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: 2024-11-20)

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

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: 37728236
DOI: 10.1021/acsinfecdis.3c00203

Experimental method

X-RAY DIFFRACTION (2.13 Å)