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PDBsum entry 2pv6
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Viral protein
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PDB id
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2pv6
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Immunity
28:52-63
(2008)
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PubMed id:
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HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane.
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Z.Y.Sun,
K.J.Oh,
M.Kim,
J.Yu,
V.Brusic,
L.Song,
Z.Qiao,
J.H.Wang,
G.Wagner,
E.L.Reinherz.
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ABSTRACT
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Although rarely elicited during natural human infection, the most broadly
neutralizing antibodies (BNAbs) against diverse human immunodeficiency virus
(HIV)-1 strains target the membrane-proximal ectodomain region (MPER) of viral
gp41. To gain insight into MPER antigenicity, immunogenicity, and viral
function, we studied its structure in the lipid environment by a combination of
nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and
surface plasmon resonance (SPR) techniques. The analyses revealed a tilted
N-terminal alpha helix (aa 664-672) connected via a short hinge to a flat
C-terminal helical segment (675-683). This metastable L-shaped structure is
immersed in viral membrane and, therefore, less accessible to immune attack.
Nonetheless, the 4E10 BNAb extracts buried W672 and F673 after initial encounter
with the surface-embedded MPER. The data suggest how BNAbs may perturb
tryptophan residue-associated viral fusion involving the mobile N-terminal MPER
segment and, given conservation of MPER sequences in HIV-1, HIV-2, and SIV, have
important implications for structure-guided vaccine design.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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B.Apellániz,
A.García-Sáez,
S.Nir,
and
J.L.Nieva
(2011).
Destabilization exerted by peptides derived from the membrane-proximal external region of HIV-1 gp41 in lipid vesicles supporting fluid phase coexistence.
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Biochim Biophys Acta,
1808,
1797-1805.
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C.R.Gregor,
E.Cerasoli,
P.R.Tulip,
M.G.Ryadnov,
G.J.Martyna,
and
J.Crain
(2011).
Autonomous folding in the membrane proximal HIV peptide gp41(659-671): pH tuneability at micelle interfaces.
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Phys Chem Chem Phys,
13,
127-135.
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M.Bomsel,
D.Tudor,
A.S.Drillet,
A.Alfsen,
Y.Ganor,
M.G.Roger,
N.Mouz,
M.Amacker,
A.Chalifour,
L.Diomede,
G.Devillier,
Z.Cong,
Q.Wei,
H.Gao,
C.Qin,
G.B.Yang,
R.Zurbriggen,
L.Lopalco,
and
S.Fleury
(2011).
Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges.
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Immunity,
34,
269-280.
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M.Caffrey
(2011).
HIV envelope: challenges and opportunities for development of entry inhibitors.
|
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Trends Microbiol,
19,
191-197.
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M.Kim,
Z.Y.Sun,
K.D.Rand,
X.Shi,
L.Song,
Y.Cheng,
A.F.Fahmy,
S.Majumdar,
G.Ofek,
Y.Yang,
P.D.Kwong,
J.H.Wang,
J.R.Engen,
G.Wagner,
and
E.L.Reinherz
(2011).
Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization.
|
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Nat Struct Mol Biol,
18,
1235-1243.
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B.E.Correia,
Y.E.Ban,
M.A.Holmes,
H.Xu,
K.Ellingson,
Z.Kraft,
C.Carrico,
E.Boni,
D.N.Sather,
C.Zenobia,
K.Y.Burke,
T.Bradley-Hewitt,
J.F.Bruhn-Johannsen,
O.Kalyuzhniy,
D.Baker,
R.K.Strong,
L.Stamatatos,
and
W.R.Schief
(2010).
Computational design of epitope-scaffolds allows induction of antibodies specific for a poorly immunogenic HIV vaccine epitope.
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Structure,
18,
1116-1126.
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PDB codes:
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D.P.Leaman,
H.Kinkead,
and
M.B.Zwick
(2010).
In-solution virus capture assay helps deconstruct heterogeneous antibody recognition of human immunodeficiency virus type 1.
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J Virol,
84,
3382-3395.
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E.M.Scherer,
D.P.Leaman,
M.B.Zwick,
A.J.McMichael,
and
D.R.Burton
(2010).
Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions.
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Proc Natl Acad Sci U S A,
107,
1529-1534.
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G.Ofek,
F.J.Guenaga,
W.R.Schief,
J.Skinner,
D.Baker,
R.Wyatt,
and
P.D.Kwong
(2010).
Elicitation of structure-specific antibodies by epitope scaffolds.
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Proc Natl Acad Sci U S A,
107,
17880-17887.
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PDB codes:
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G.Ofek,
K.McKee,
Y.Yang,
Z.Y.Yang,
J.Skinner,
F.J.Guenaga,
R.Wyatt,
M.B.Zwick,
G.J.Nabel,
J.R.Mascola,
and
P.D.Kwong
(2010).
Relationship between antibody 2F5 neutralization of HIV-1 and hydrophobicity of its heavy chain third complementarity-determining region.
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J Virol,
84,
2955-2962.
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H.Xu,
L.Song,
M.Kim,
M.A.Holmes,
Z.Kraft,
G.Sellhorn,
E.L.Reinherz,
L.Stamatatos,
and
R.K.Strong
(2010).
Interactions between lipids and human anti-HIV antibody 4E10 can be reduced without ablating neutralizing activity.
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J Virol,
84,
1076-1088.
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PDB code:
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J.D.Steckbeck,
C.Sun,
T.J.Sturgeon,
and
R.C.Montelaro
(2010).
Topology of the C-terminal tail of HIV-1 gp41: differential exposure of the Kennedy epitope on cell and viral membranes.
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PLoS One,
5,
e15261.
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J.Liu,
Y.Deng,
Q.Li,
A.K.Dey,
J.P.Moore,
and
M.Lu
(2010).
Role of a putative gp41 dimerization domain in human immunodeficiency virus type 1 membrane fusion.
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J Virol,
84,
201-209.
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PDB codes:
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J.Pietzsch,
J.F.Scheid,
H.Mouquet,
M.S.Seaman,
C.C.Broder,
and
M.C.Nussenzweig
(2010).
Anti-gp41 antibodies cloned from HIV-infected patients with broadly neutralizing serologic activity.
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J Virol,
84,
5032-5042.
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K.J.Nakamura,
J.S.Gach,
L.Jones,
K.Semrau,
J.Walter,
F.Bibollet-Ruche,
J.M.Decker,
L.Heath,
W.D.Decker,
M.Sinkala,
C.Kankasa,
D.Thea,
J.Mullins,
L.Kuhn,
M.B.Zwick,
and
G.M.Aldrovandi
(2010).
4E10-resistant HIV-1 isolated from four subjects with rare membrane-proximal external region polymorphisms.
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PLoS One,
5,
e9786.
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L.M.Walker,
and
D.R.Burton
(2010).
Rational antibody-based HIV-1 vaccine design: current approaches and future directions.
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Curr Opin Immunol,
22,
358-366.
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M.D.Hicar,
X.Chen,
B.Briney,
J.Hammonds,
J.J.Wang,
S.Kalams,
P.W.Spearman,
and
J.E.Crowe
(2010).
Pseudovirion particles bearing native HIV envelope trimers facilitate a novel method for generating human neutralizing monoclonal antibodies against HIV.
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J Acquir Immune Defic Syndr,
54,
223-235.
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R.L.Rich,
and
D.G.Myszka
(2010).
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
|
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J Mol Recognit,
23,
1.
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S.Hearty,
P.J.Conroy,
B.V.Ayyar,
B.Byrne,
and
R.O'Kennedy
(2010).
Surface plasmon resonance for vaccine design and efficacy studies: recent applications and future trends.
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Expert Rev Vaccines,
9,
645-664.
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S.Ingale,
J.S.Gach,
M.B.Zwick,
and
P.E.Dawson
(2010).
Synthesis and analysis of the membrane proximal external region epitopes of HIV-1.
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J Pept Sci,
16,
716-722.
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V.Buzon,
G.Natrajan,
D.Schibli,
F.Campelo,
M.M.Kozlov,
and
W.Weissenhorn
(2010).
Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.
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PLoS Pathog,
6,
e1000880.
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PDB code:
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X.Shen,
S.M.Dennison,
P.Liu,
F.Gao,
F.Jaeger,
D.C.Montefiori,
L.Verkoczy,
B.F.Haynes,
S.M.Alam,
and
G.D.Tomaras
(2010).
Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution.
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Proc Natl Acad Sci U S A,
107,
5972-5977.
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A.S.Veiga,
L.K.Pattenden,
J.M.Fletcher,
M.A.Castanho,
and
M.I.Aguilar
(2009).
Interactions of HIV-1 antibodies 2F5 and 4E10 with a gp41 epitope prebound to host and viral membrane model systems.
|
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Chembiochem,
10,
1032-1044.
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D.S.Watson,
and
F.C.Szoka
(2009).
Role of lipid structure in the humoral immune response in mice to covalent lipid-peptides from the membrane proximal region of HIV-1 gp41.
|
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Vaccine,
27,
4672-4683.
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E.S.Gray,
M.C.Madiga,
P.L.Moore,
K.Mlisana,
S.S.Abdool Karim,
J.M.Binley,
G.M.Shaw,
J.R.Mascola,
and
L.Morris
(2009).
Broad neutralization of human immunodeficiency virus type 1 mediated by plasma antibodies against the gp41 membrane proximal external region.
|
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J Virol,
83,
11265-11274.
|
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F.Naider,
and
J.Anglister
(2009).
Peptides in the treatment of AIDS.
|
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Curr Opin Struct Biol,
19,
473-482.
|
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G.R.Matyas,
L.Wieczorek,
Z.Beck,
C.Ochsenbauer-Jambor,
J.C.Kappes,
N.L.Michael,
V.R.Polonis,
and
C.R.Alving
(2009).
Neutralizing antibodies induced by liposomal HIV-1 glycoprotein 41 peptide simultaneously bind to both the 2F5 or 4E10 epitope and lipid epitopes.
|
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AIDS,
23,
2069-2077.
|
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J.Liu,
Y.Deng,
A.K.Dey,
J.P.Moore,
and
M.Lu
(2009).
Structure of the HIV-1 gp41 membrane-proximal ectodomain region in a putative prefusion conformation.
|
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Biochemistry,
48,
2915-2923.
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PDB code:
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J.S.Klein,
P.N.Gnanapragasam,
R.P.Galimidi,
C.P.Foglesong,
A.P.West,
and
P.J.Bjorkman
(2009).
Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10.
|
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Proc Natl Acad Sci U S A,
106,
7385-7390.
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L.G.Perez,
M.R.Costa,
C.A.Todd,
B.F.Haynes,
and
D.C.Montefiori
(2009).
Utilization of immunoglobulin G Fc receptors by human immunodeficiency virus type 1: a specific role for antibodies against the membrane-proximal external region of gp41.
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J Virol,
83,
7397-7410.
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L.Verkoczy,
M.A.Moody,
T.M.Holl,
H.Bouton-Verville,
R.M.Scearce,
J.Hutchinson,
S.M.Alam,
G.Kelsoe,
and
B.F.Haynes
(2009).
Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.
|
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PLoS One,
4,
e7215.
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R.Pejchal,
J.S.Gach,
F.M.Brunel,
R.M.Cardoso,
R.L.Stanfield,
P.E.Dawson,
D.R.Burton,
M.B.Zwick,
and
I.A.Wilson
(2009).
A conformational switch in human immunodeficiency virus gp41 revealed by the structures of overlapping epitopes recognized by neutralizing antibodies.
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J Virol,
83,
8451-8462.
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PDB code:
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S.Bryson,
J.P.Julien,
R.C.Hynes,
and
E.F.Pai
(2009).
Crystallographic definition of the epitope promiscuity of the broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2F5: vaccine design implications.
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J Virol,
83,
11862-11875.
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PDB codes:
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S.M.Dennison,
S.M.Stewart,
K.C.Stempel,
H.X.Liao,
B.F.Haynes,
and
S.M.Alam
(2009).
Stable docking of neutralizing human immunodeficiency virus type 1 gp41 membrane-proximal external region monoclonal antibodies 2F5 and 4E10 is dependent on the membrane immersion depth of their epitope regions.
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J Virol,
83,
10211-10223.
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S.M.O'Rourke,
B.Schweighardt,
W.G.Scott,
T.Wrin,
D.P.Fonseca,
F.Sinangil,
and
P.W.Berman
(2009).
Novel ring structure in the gp41 trimer of human immunodeficiency virus type 1 that modulates sensitivity and resistance to broadly neutralizing antibodies.
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J Virol,
83,
7728-7738.
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V.Martinez,
M.C.Diemert,
M.Braibant,
V.Potard,
J.L.Charuel,
F.Barin,
D.Costagliola,
E.Caumes,
J.P.Clauvel,
B.Autran,
and
L.Musset
(2009).
Anticardiolipin antibodies in HIV infection are independently associated with antibodies to the membrane proximal external region of gp41 and with cell-associated HIV DNA and immune activation.
|
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Clin Infect Dis,
48,
123-132.
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B.F.Haynes,
and
R.J.Shattock
(2008).
Critical issues in mucosal immunity for HIV-1 vaccine development.
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J Allergy Clin Immunol,
122,
3.
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B.F.Haynes,
and
S.M.Alam
(2008).
HIV-1 hides an Achilles' heel in virion lipids.
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Immunity,
28,
10-12.
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D.H.Barouch
(2008).
Challenges in the development of an HIV-1 vaccine.
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Nature,
455,
613-619.
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J.M.White,
S.E.Delos,
M.Brecher,
and
K.Schornberg
(2008).
Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme.
|
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Crit Rev Biochem Mol Biol,
43,
189-219.
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M.A.Moody,
and
B.F.Haynes
(2008).
Antigen-specific B cell detection reagents: use and quality control.
|
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Cytometry A,
73,
1086-1092.
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N.Huarte,
M.Lorizate,
R.Maeso,
R.Kunert,
R.Arranz,
J.M.Valpuesta,
and
J.L.Nieva
(2008).
The broadly neutralizing anti-human immunodeficiency virus type 1 4E10 monoclonal antibody is better adapted to membrane-bound epitope recognition and blocking than 2F5.
|
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J Virol,
82,
8986-8996.
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P.Zhu,
H.Winkler,
E.Chertova,
K.A.Taylor,
and
K.H.Roux
(2008).
Cryoelectron tomography of HIV-1 envelope spikes: further evidence for tripod-like legs.
|
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PLoS Pathog,
4,
e1000203.
|
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R.A.Larson,
D.Dai,
V.T.Hosack,
Y.Tan,
T.C.Bolken,
D.E.Hruby,
and
S.M.Amberg
(2008).
Identification of a broad-spectrum arenavirus entry inhibitor.
|
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J Virol,
82,
10768-10775.
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S.A.Vishwanathan,
A.Thomas,
R.Brasseur,
R.F.Epand,
E.Hunter,
and
R.M.Epand
(2008).
Large changes in the CRAC segment of gp41 of HIV do not destroy fusion activity if the segment interacts with cholesterol.
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Biochemistry,
47,
11869-11876.
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S.A.Vishwanathan,
and
E.Hunter
(2008).
Importance of the membrane-perturbing properties of the membrane-proximal external region of human immunodeficiency virus type 1 gp41 to viral fusion.
|
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J Virol,
82,
5118-5126.
|
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S.C.Harrison
(2008).
Viral membrane fusion.
|
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Nat Struct Mol Biol,
15,
690-698.
|
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
