2Q6F

Crystal structure of infectious bronchitis virus (IBV) main protease in complex with a Michael acceptor inhibitor N3

2Q6F の概要

• エントリーDOI: 10.2210/pdb2q6f/pdb
• 関連するPDBエントリー: 2Q6D 2Q6G
• 関連するBIRD辞書のPRD_ID: PRD_002214
• 分子名称: Infectious bronchitis virus (IBV) 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: coronavirus; ibv; main protease; 3c-like proteinase; michael acceptor inhibitor, hydrolase
• 由来する生物種: Infectious bronchitis virus; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 68633.48

構造登録者

Xue, X.Y.,Yang, H.T.,Xue, F.,Bartlam, M.,Rao, Z.H. (登録日: 2007-06-05, 公開日: 2008-02-12, 最終更新日: 2024-10-16)

主引用文献

Xue, X.,Yu, H.,Yang, H.,Xue, F.,Wu, Z.,Shen, W.,Li, J.,Zhou, Z.,Ding, Y.,Zhao, Q.,Zhang, X.C.,Liao, M.,Bartlam, M.,Rao, Z.
Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design.
J.Virol., 82:2515-2527, 2008

PubMed Abstract: Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M(pro)), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M(pro) and a severe acute respiratory syndrome CoV (SARS-CoV) M(pro) mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M(pro). A monomeric form of IBV M(pro) was identified for the first time in CoV M(pro) structures. A comparison of these two structures to other available M(pro) structures provides new insights for the design of substrate-based inhibitors targeting CoV M(pro)s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M(pro) and was found to demonstrate in vitro inactivation of IBV M(pro) and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M(pro).

PubMed: 18094151
DOI: 10.1128/JVI.02114-07

実験手法

X-RAY DIFFRACTION (2 Å)