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PDBsum entry 5ea3
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Cell invasion/inhibitor
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PDB id
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5ea3
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References listed in PDB file
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Key reference
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Title
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Molecular mechanism of respiratory syncytial virus fusion inhibitors.
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Authors
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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.
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Ref.
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Nat Chem Biol, 2016,
12,
87-93.
[DOI no: ]
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PubMed id
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Abstract
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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.
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