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PDBsum entry 2ymt
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Protein transport
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PDB id
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2ymt
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References listed in PDB file
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Key reference
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Title
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The hepatitis b virus pres1 domain hijacks host trafficking proteins by motif mimicry.
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Authors
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M.C.Jürgens,
J.Vörös,
G.J.Rautureau,
D.A.Shepherd,
V.E.Pye,
J.Muldoon,
C.M.Johnson,
A.E.Ashcroft,
S.M.Freund,
N.Ferguson.
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Ref.
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Nat Chem Biol, 2013,
9,
540-547.
[DOI no: ]
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PubMed id
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Abstract
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Hepatitis B virus (HBV) is an infectious, potentially lethal human pathogen.
However, there are no effective therapies for chronic HBV infections. Antiviral
development is hampered by the lack of high-resolution structures for essential
HBV protein-protein interactions. The interaction between preS1, an HBV
surface-protein domain, and its human binding partner, γ2-adaptin, subverts the
membrane-trafficking apparatus to mediate virion export. This interaction is a
putative drug target. We report here atomic-resolution descriptions of the
binding thermodynamics and structural biology of the interaction between preS1
and the EAR domain of γ2-adaptin. NMR, protein engineering, X-ray
crystallography and MS showed that preS1 contains multiple γ2-EAR-binding
motifs that mimic the membrane-trafficking motifs (and binding modes) of host
proteins. These motifs localize together to a relatively rigid, functionally
important region of preS1, an intrinsically disordered protein. The
preS1-γ2-EAR interaction was relatively weak and efficiently outcompeted by a
synthetic peptide. Our data provide the structural road map for developing
peptidomimetic antivirals targeting the γ2-EAR-preS1 interaction.
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