6WXC

Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2 in the Complex with potential repurposing drug Tipiracil

6WXC の概要

• エントリーDOI: 10.2210/pdb6wxc/pdb
• 関連するPDBエントリー: 6VWW 6W01 6WLC
• 分子名称: Uridylate-specific endoribonuclease, 5-CHLORO-6-(1-(2-IMINOPYRROLIDINYL) METHYL) URACIL, PHOSPHATE ION, ... (6 entities in total)
• 機能のキーワード: sars corona virus 2, endoribonuclease, refurbishing drug, covid-19, structural genomics, center for structural genomics of infectious diseases, csgid, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84732.45

構造登録者

Kim, Y.,Maltseva, N.,Jedrzejczak, R.,Welk, L.,Endres, M.,Chang, C.,Michalska, K.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (登録日: 2020-05-10, 公開日: 2020-05-20, 最終更新日: 2023-10-18)

主引用文献

Kim, Y.,Wower, J.,Maltseva, N.,Chang, C.,Jedrzejczak, R.,Wilamowski, M.,Kang, S.,Nicolaescu, V.,Randall, G.,Michalska, K.,Joachimiak, A.
Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2.
Commun Biol, 4:193-193, 2021

PubMed Abstract: SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family that is highly conserved in coronaviruses. As endoribonuclease activity seems to be responsible for the interference with the innate immune response, Nsp15 emerges as an attractive target for therapeutic intervention. Here we report the first structures with bound nucleotides and show how the enzyme specifically recognizes uridine moiety. In addition to a uridine site we present evidence for a second base binding site that can accommodate any base. The structure with a transition state analog, uridine vanadate, confirms interactions key to catalytic mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. This acquired knowledge was instrumental in identifying Tipiracil, an FDA approved drug that is used in the treatment of colorectal cancer, as a potential anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays, we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme's active site. Our findings provide new insights for the development of uracil scaffold-based drugs.

PubMed: 33564093
DOI: 10.1038/s42003-021-01735-9

実験手法

X-RAY DIFFRACTION (1.85 Å)