9AZX

Crystal structure of SARS-CoV-2 (Covid-19) Nsp3 macrodomain in complex with NDPr

これはPDB形式変換不可エントリーです。

9AZX の概要

• エントリーDOI: 10.2210/pdb9azx/pdb
• 分子名称: Non-structural protein 3, {(2R,3S,4R,5R)-5-[(8S)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-cyano-3,4-dihydroxyoxolan-2-yl}methyl [(2R,3S,4R,5R)-3,4,5-trihydroxyoxolan-2-yl]methyl dihydrogen diphosphate (3 entities in total)
• 機能のキーワード: viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 56577.32

構造登録者

Wallace, S.D.,Bagde, S.R.,Fromme, J.C. (登録日: 2024-03-11, 公開日: 2024-05-01, 最終更新日: 2024-05-29)

主引用文献

Peng, K.,Wallace, S.D.,Bagde, S.R.,Shang, J.,Anmangandla, A.,Jana, S.,Fromme, J.C.,Lin, H.
GS-441524-Diphosphate-Ribose Derivatives as Nanomolar Binders and Fluorescence Polarization Tracers for SARS-CoV-2 and Other Viral Macrodomains.
Acs Chem.Biol., 19:1093-1105, 2024

PubMed Abstract: Viral macrodomains that can bind to or hydrolyze protein adenosine diphosphate ribosylation (ADP-ribosylation) have emerged as promising targets for antiviral drug development. Many inhibitor development efforts have been directed against the severe acute respiratory syndrome coronavirus 2 macrodomain 1 (SARS-CoV-2 Mac1). However, potent inhibitors for viral macrodomains are still lacking, with the best inhibitors still in the micromolar range. Based on , a remdesivir precursor, and our previous studies, we have designed and synthesized potent binders of SARS-CoV-2 Mac1 and other viral macrodomains including those of Middle East respiratory syndrome coronavirus (MERS-CoV), Venezuelan equine encephalitis virus (VEEV), and Chikungunya virus (CHIKV). We show that the 1'-CN group of promotes binding to all four viral macrodomains tested while capping the 1″-OH of -diphosphate-ribose with a simple phenyl ring further contributes to binding. Incorporating these two structural features, the best binders show 20- to 6000-fold increases in binding affinity over ADP-ribose for SARS-CoV-2, MERS-CoV, VEEV, and CHIKV macrodomains. Moreover, building on these potent binders, we have developed two highly sensitive fluorescence polarization tracers that only require nanomolar proteins and can effectively resolve the binding affinities of nanomolar inhibitors. Our findings and probes described here will facilitate future development of more potent viral macrodomain inhibitors.

PubMed: 38646883
DOI: 10.1021/acschembio.4c00027

実験手法

X-RAY DIFFRACTION (1.395 Å)