5GWY

Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design

5GWY の概要

• エントリーDOI: 10.2210/pdb5gwy/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002214
• 分子名称: main protease, N-[(5-METHYLISOXAZOL-3-YL)CARBONYL]ALANYL-L-VALYL-N~1~-((1R,2Z)-4-(BENZYLOXY)-4-OXO-1-{[(3R)-2-OXOPYRROLIDIN-3-YL]METHYL}BUT-2-ENYL)-L-LEUCINAMIDE (3 entities in total)
• 機能のキーワード: hcov-nl63, main protease, inhibitor, complex, drug design, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human coronavirus NL63 (HCoV-NL63); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 67710.74

構造登録者

Wang, F.,Chen, C.,Tan, W.,Yang, K.,Yang, H. (登録日: 2016-09-14, 公開日: 2017-09-20, 最終更新日: 2024-11-20)

主引用文献

Wang, F.,Chen, C.,Tan, W.,Yang, K.,Yang, H.
Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design.
Sci Rep, 6:22677-22677, 2016

PubMed Abstract: First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis, and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (M(pro)), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, M(pro) has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 M(pro) in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with M(pro)s from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 M(pro) provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.

PubMed: 26948040
DOI: 10.1038/srep22677

実験手法

X-RAY DIFFRACTION (2.852 Å)