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PDBsum entry 2me4
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Membrane protein
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PDB id
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2me4
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References listed in PDB file
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Key reference
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Title
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Disruption of helix-Capping residues 671 and 674 reveals a role in HIV-1 entry for a specialized hinge segment of the membrane proximal external region of gp41.
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Authors
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Z.Y.Sun,
Y.Cheng,
M.Kim,
L.Song,
J.Choi,
U.J.Kudahl,
V.Brusic,
B.Chowdhury,
L.Yu,
M.S.Seaman,
G.Bellot,
W.M.Shih,
G.Wagner,
E.L.Reinherz.
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Ref.
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J Mol Biol, 2014,
426,
1095-1108.
[DOI no: ]
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PubMed id
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Abstract
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HIV-1 (human immunodeficiency virus type 1) uses its trimeric gp160 envelope
(Env) protein consisting of non-covalently associated gp120 and gp41 subunits to
mediate entry into human T lymphocytes. A facile virus fusion mechanism
compensates for the sparse Env copy number observed on viral particles and
includes a 22-amino-acid, lentivirus-specific adaptation at the gp41 base (amino
acid residues 662-683), termed the membrane proximal external region (MPER). We
show by NMR and EPR that the MPER consists of a structurally conserved pair of
viral lipid-immersed helices separated by a hinge with tandem joints that can be
locked by capping residues between helices. This design fosters efficient HIV-1
fusion via interconverting structures while, at the same time, affording immune
escape. Disruption of both joints by double alanine mutations at Env positions
671 and 674 (AA) results in attenuation of Env-mediated cell-cell fusion and
hemifusion, as well as viral infectivity mediated by both CD4-dependent and
CD4-independent viruses. The potential mechanism of disruption was revealed by
structural analysis of MPER conformational changes induced by AA mutation. A
deeper acyl chain-buried MPER middle section and the elimination of cross-hinge
rigid-body motion almost certainly impede requisite structural rearrangements
during the fusion process, explaining the absence of MPER AA variants among all
known naturally occurring HIV-1 viral sequences. Furthermore, those broadly
neutralization antibodies directed against the HIV-1 MPER exploit the tandem
joint architecture involving helix capping, thereby disrupting hinge function.
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