PDBsum entry 5ea3

Cell invasion/inhibitor

PDB id: 5ea3

Contents

Protein chain

419 a.a.

Ligands

NHE

SO4 ×6

5NK

Waters ×36

PDB id:

5ea3

Name:

Cell invasion/inhibitor

Title:

Crystal structure of inhibitor jnj-2408068 in complex with prefusion rsv f glycoprotein

Structure:

Fusion glycoprotein f0. Chain: f. Fragment: rsv f ectodomain (unp residues 1-513). Synonym: protein f. Engineered: yes. Mutation: yes

Source:

Human respiratory syncytial virus a (strain a2). Organism_taxid: 11259. Strain: a2. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293 freestyle.

Resolution:

2.75Å R-factor: 0.200 R-free: 0.229

Authors:

M.B.Battles,J.S.Mclellan,E.Arnoult,J.P.Langedijk,D.Roymans

Key ref:

M.B.Battles et al. (2016). Molecular mechanism of respiratory syncytial virus fusion inhibitors. Nat Chem Biol, 12, 87-93. PubMed id: 26641933 DOI: 10.1038/nchembio.1982

Date:

15-Oct-15 Release date: 09-Dec-15

Protein chain

P03420  (FUS_HRSVA) -  Fusion glycoprotein F0 from Human respiratory syncytial virus A (strain A2)

Seq: 574 a.a.

Struc: 419 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

DOI no: 10.1038/nchembio.1982

Nat Chem Biol 12:87-93 (2016)

PubMed id: 26641933

Molecular mechanism of respiratory syncytial virus fusion inhibitors.

M.B.Battles, J.P.Langedijk, P.Furmanova-Hollenstein, S.Chaiwatpongsakorn, H.M.Costello, L.Kwanten, L.Vranckx, P.Vink, S.Jaensch, T.H.Jonckers, A.Koul, E.Arnoult, M.E.Peeples, D.Roymans, J.S.McLellan.

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.