5EA3

Crystal Structure of Inhibitor JNJ-2408068 in Complex with Prefusion RSV F Glycoprotein

Summary for 5EA3

• Entry DOI: 10.2210/pdb5ea3/pdb
• Related: 4MMU 5EA4 5EA5 5EA6 5EA7 5EA8
• Descriptor: Fusion glycoprotein F0, 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID, SULFATE ION, ... (5 entities in total)
• Functional Keywords: class i viral fusion protein, fusion, respiratory syncytial virus, prefusion, viral protein, fusion inhibitor, cell invasion-inhibitor complex, cell invasion/inhibitor
• Biological source: Human respiratory syncytial virus A (strain A2)
• Total number of polymer chains: 1
• Total formula weight: 64396.52

Authors

Battles, M.B.,McLellan, J.S.,Arnoult, E.,Langedijk, J.P.,Roymans, D. (deposition date: 2015-10-15, release date: 2015-12-09, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.75 Å)