8F4S

Crystal Structure of the SARS-CoV-2 2'-O-Methyltransferase with Compound 5a bound to the Cryptic Pocket of nsp16

8F4S の概要

• エントリーDOI: 10.2210/pdb8f4s/pdb
• 分子名称: 2'-O-methyltransferase, Non-structural protein 10, SODIUM ION, ... (7 entities in total)
• 機能のキーワード: csbid, center for structural biology of infectious diseases, methyl transferase, structural genomics, transferase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49421.74

構造登録者

Minasov, G.,Shuvalova, L.,Brunzelle, J.S.,Rosas-Lemus, M.,Kiryukhina, O.,Satchell, K.J.F.,Center for Structural Biology of Infectious Diseases (CSBID) (登録日: 2022-11-11, 公開日: 2023-10-18, 最終更新日: 2026-03-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.15 Å)