5EA7

Crystal Structure of Inhibitor BMS-433771 in Complex with Prefusion RSV F Glycoprotein

5EA7 の概要

• エントリーDOI: 10.2210/pdb5ea7/pdb
• 関連するPDBエントリー: 4MMU 5EA3 5EA4 5EA5 5EA6 5EA8
• 分子名称: Fusion glycoprotein F0, SULFATE ION, 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: class i viral fusion protein, fusion, respiratory syncytial virus, prefusion, viral protein, fusion inhibitor, cell invasion-inhibitor complex, cell invasion/inhibitor
• 由来する生物種: Human respiratory syncytial virus A (strain A2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 64283.39

構造登録者

Battles, M.B.,McLellan, J.S.,Arnoult, E.,Roymans, D.,Langedijk, J.P. (登録日: 2015-10-15, 公開日: 2015-12-09, 最終更新日: 2023-09-27)

主引用文献

Battles, M.B.,Langedijk, J.P.,Furmanova-Hollenstein, P.,Chaiwatpongsakorn, S.,Costello, H.M.,Kwanten, L.,Vranckx, L.,Vink, P.,Jaensch, S.,Jonckers, T.H.,Koul, A.,Arnoult, E.,Peeples, M.E.,Roymans, D.,McLellan, J.S.
Molecular mechanism of respiratory syncytial virus fusion inhibitors.
Nat.Chem.Biol., 12:87-93, 2016

PubMed Abstract: Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.

PubMed: 26641933
DOI: 10.1038/nchembio.1982

実験手法

X-RAY DIFFRACTION (2.851 Å)