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214 a.a.
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237 a.a.
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13 a.a.
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* Residue conservation analysis
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PDB id:
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Viral protein/immune system
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Title:
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Crystal structure of the broadly neutralizing anti-HIV-1 antibody 2f5 in complex with a gp41 11mer epitope
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Structure:
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Anti-HIV-1 antibody 2f5 light chain. Chain: l. Engineered: yes. Anti-HIV-1 antibody 2f5 heavy chain. Chain: h. Engineered: yes. Envelope glycoprotein gp41. Chain: p. Fragment: transmembrane glycoprotein (residues 659-669).
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cb-f7. Other_details: heteromyeloma cell line cb-f7 fused with peripheral blood mononuclear cells. Synthetic: yes.
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Biol. unit:
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Trimer (from
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Resolution:
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2.10Å
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R-factor:
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0.200
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R-free:
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0.233
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Authors:
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G.Ofek,M.Tang,A.Sambor,H.Katinger,J.R.Mascola,R.Wyatt,P.D.Kwong
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Key ref:
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G.Ofek
et al.
(2004).
Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope.
J Virol,
78,
10724-10737.
PubMed id:
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Date:
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04-Jun-04
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Release date:
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05-Oct-04
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PROCHECK
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Headers
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References
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No UniProt id for this chain
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J Virol
78:10724-10737
(2004)
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PubMed id:
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Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope.
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G.Ofek,
M.Tang,
A.Sambor,
H.Katinger,
J.R.Mascola,
R.Wyatt,
P.D.Kwong.
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ABSTRACT
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The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein
of human immunodeficiency virus type 1 (HIV-1) is the target of three of the
five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have
determined crystal structures of the antigen-binding fragment for one of these
antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41
membrane-proximal region, at 2.0-, 2.1-, and 2.2-A resolutions, respectively.
The structures reveal an extended gp41 conformation, which stretches over 30 A
in length. Contacts are made with five complementarity-determining regions of
the antibody as well as with nonpolymorphic regions. Only one exclusive charged
face of the gp41 epitope is bound by 2F5, while the nonbound face, which is
hydrophobic, may be hidden due to occlusion by other portions of the ectodomain.
The structures reveal that the 2F5 antibody is uniquely built to bind to an
epitope that is proximal to a membrane surface and in a manner mostly unaffected
by large-scale steric hindrance. Biochemical studies with proteoliposomes
confirm the importance of lipid membrane and hydrophobic context in the binding
of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody
that recognizes the membrane-proximal region of gp41. Based on these structural
and biochemical results, immunization strategies for eliciting 2F5- and
4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed.
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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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|
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|
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J.Huang,
G.Ofek,
L.Laub,
M.K.Louder,
N.A.Doria-Rose,
N.S.Longo,
H.Imamichi,
R.T.Bailer,
B.Chakrabarti,
S.K.Sharma,
S.M.Alam,
T.Wang,
Y.Yang,
B.Zhang,
S.A.Migueles,
R.Wyatt,
B.F.Haynes,
P.D.Kwong,
J.R.Mascola,
and
M.Connors
(2012).
Broad and potent neutralization of HIV-1 by a gp41-specific human antibody.
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Nature,
491,
406-412.
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PDB code:
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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.
|
| |
Phys Chem Chem Phys,
13,
127-135.
|
 |
|
|
|
|
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D.K.Wijesundara,
R.J.Jackson,
I.A.Ramshaw,
and
C.Ranasinghe
(2011).
Human immunodeficiency virus-1 vaccine design: where do we go now?
|
| |
Immunol Cell Biol,
89,
367-374.
|
 |
|
|
|
|
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D.Lamb,
A.W.Schüttelkopf,
D.M.van Aalten,
and
D.W.Brighty
(2011).
Charge-surrounded pockets and electrostatic interactions with small ions modulate the activity of retroviral fusion proteins.
|
| |
PLoS Pathog,
7,
e1001268.
|
 |
|
PDB code:
|
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|
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|
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F.Breden,
C.Lepik,
N.S.Longo,
M.Montero,
P.E.Lipsky,
and
J.K.Scott
(2011).
Comparison of antibody repertoires produced by HIV-1 infection, other chronic and acute infections, and systemic autoimmune disease.
|
| |
PLoS One,
6,
e16857.
|
 |
|
|
|
|
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J.Guenaga,
P.Dosenovic,
G.Ofek,
D.Baker,
W.R.Schief,
P.D.Kwong,
G.B.Karlsson Hedestam,
and
R.T.Wyatt
(2011).
Heterologous Epitope-Scaffold Prime∶Boosting Immuno-Focuses B Cell Responses to the HIV-1 gp41 2F5 Neutralization Determinant.
|
| |
PLoS One,
6,
e16074.
|
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|
|
|
|
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J.Wang,
P.Tong,
L.Lu,
L.Zhou,
L.Xu,
S.Jiang,
and
Y.H.Chen
(2011).
HIV-1 gp41 core with exposed membrane-proximal external region inducing broad HIV-1 neutralizing antibodies.
|
| |
PLoS One,
6,
e18233.
|
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|
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|
|
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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.
|
| |
Nat Struct Mol Biol,
18,
1235-1243.
|
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|
|
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|
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X.Shen,
and
G.D.Tomaras
(2011).
Alterations of the B-cell response by HIV-1 replication.
|
| |
Curr HIV/AIDS Rep,
8,
23-30.
|
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|
|
|
|
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A.A.Waheed,
S.D.Ablan,
R.C.Sowder,
J.D.Roser,
C.P.Schaffner,
E.Chertova,
and
E.O.Freed
(2010).
Effect of mutations in the human immunodeficiency virus type 1 protease on cleavage of the gp41 cytoplasmic tail.
|
| |
J Virol,
84,
3121-3126.
|
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|
|
|
|
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A.J.McMichael,
P.Borrow,
G.D.Tomaras,
N.Goonetilleke,
and
B.F.Haynes
(2010).
The immune response during acute HIV-1 infection: clues for vaccine development.
|
| |
Nat Rev Immunol,
10,
11-23.
|
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|
|
|
|
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A.Mader,
and
R.Kunert
(2010).
Humanization strategies for an anti-idiotypic antibody mimicking HIV-1 gp41.
|
| |
Protein Eng Des Sel,
23,
947-954.
|
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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.
|
| |
Structure,
18,
1116-1126.
|
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PDB codes:
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|
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B.F.Haynes,
N.I.Nicely,
and
S.M.Alam
(2010).
HIV-1 autoreactive antibodies: are they good or bad for HIV-1 prevention?
|
| |
Nat Struct Mol Biol,
17,
543-545.
|
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|
|
|
|
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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.
|
| |
J Virol,
84,
3382-3395.
|
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|
|
|
|
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D.R.Burton
(2010).
Scaffolding to build a rational vaccine design strategy.
|
| |
Proc Natl Acad Sci U S A,
107,
17859-17860.
|
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|
|
|
|
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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.
|
| |
Proc Natl Acad Sci U S A,
107,
1529-1534.
|
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|
|
|
|
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G.Frey,
J.Chen,
S.Rits-Volloch,
M.M.Freeman,
S.Zolla-Pazner,
and
B.Chen
(2010).
Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies.
|
| |
Nat Struct Mol Biol,
17,
1486-1491.
|
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PDB code:
|
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|
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|
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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.
|
| |
Proc Natl Acad Sci U S A,
107,
17880-17887.
|
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PDB codes:
|
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|
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|
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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.
|
| |
J Virol,
84,
2955-2962.
|
 |
|
|
|
|
 |
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.
|
| |
J Virol,
84,
1076-1088.
|
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PDB code:
|
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|
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|
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J.A.Hoxie
(2010).
Toward an antibody-based HIV-1 vaccine.
|
| |
Annu Rev Med,
61,
135-152.
|
 |
|
|
|
|
 |
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.
|
| |
J Virol,
84,
201-209.
|
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|
PDB codes:
|
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|
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|
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J.Nie,
A.Song,
S.Xu,
X.Li,
and
Y.Wang
(2010).
The effect of human immunodeficiency virus type 1 (HIV-1) gp41 variability on antibody detection.
|
| |
Arch Virol,
155,
1813-1822.
|
 |
|
|
|
|
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J.P.Julien,
N.Huarte,
R.Maeso,
S.G.Taneva,
A.Cunningham,
J.L.Nieva,
and
E.F.Pai
(2010).
Ablation of the complementarity-determining region H3 apex of the anti-HIV-1 broadly neutralizing antibody 2F5 abrogates neutralizing capacity without affecting core epitope binding.
|
| |
J Virol,
84,
4136-4147.
|
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|
|
|
|
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J.R.Mascola,
and
D.C.Montefiori
(2010).
The role of antibodies in HIV vaccines.
|
| |
Annu Rev Immunol,
28,
413-444.
|
 |
|
|
|
|
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J.S.Klein,
and
P.J.Bjorkman
(2010).
Few and far between: how HIV may be evading antibody avidity.
|
| |
PLoS Pathog,
6,
e1000908.
|
 |
|
|
|
|
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K.J.Doores,
Z.Fulton,
V.Hong,
M.K.Patel,
C.N.Scanlan,
M.R.Wormald,
M.G.Finn,
D.R.Burton,
I.A.Wilson,
and
B.G.Davis
(2010).
A nonself sugar mimic of the HIV glycan shield shows enhanced antigenicity.
|
| |
Proc Natl Acad Sci U S A,
107,
17107-17112.
|
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PDB codes:
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L.J.Gamble,
and
Q.L.Matthews
(2010).
Current progress in the development of a prophylactic vaccine for HIV-1.
|
| |
Drug Des Devel Ther,
5,
9.
|
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|
|
|
|
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L.M.Walker,
and
D.R.Burton
(2010).
Rational antibody-based HIV-1 vaccine design: current approaches and future directions.
|
| |
Curr Opin Immunol,
22,
358-366.
|
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|
|
|
|
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M.Lapelosa,
G.F.Arnold,
E.Gallicchio,
E.Arnold,
and
R.M.Levy
(2010).
Antigenic characteristics of rhinovirus chimeras designed in silico for enhanced presentation of HIV-1 gp41 epitopes [corrected].
|
| |
J Mol Biol,
397,
752-766.
|
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|
|
|
|
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M.Pancera,
J.S.McLellan,
X.Wu,
J.Zhu,
A.Changela,
S.D.Schmidt,
Y.Yang,
T.Zhou,
S.Phogat,
J.R.Mascola,
and
P.D.Kwong
(2010).
Crystal structure of PG16 and chimeric dissection with somatically related PG9: structure-function analysis of two quaternary-specific antibodies that effectively neutralize HIV-1.
|
| |
J Virol,
84,
8098-8110.
|
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PDB codes:
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N.I.Nicely,
S.M.Dennison,
L.Spicer,
R.M.Scearce,
G.Kelsoe,
Y.Ueda,
H.Chen,
H.X.Liao,
S.M.Alam,
and
B.F.Haynes
(2010).
Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region.
|
| |
Nat Struct Mol Biol,
17,
1492-1494.
|
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PDB code:
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|
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P.Wang,
and
X.Yang
(2010).
Neutralization efficiency is greatly enhanced by bivalent binding of an antibody to epitopes in the V4 region and the membrane-proximal external region within one trimer of human immunodeficiency virus type 1 glycoproteins.
|
| |
J Virol,
84,
7114-7123.
|
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|
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|
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Q.L.Matthews,
A.Fatima,
Y.Tang,
B.A.Perry,
Y.Tsuruta,
S.Komarova,
L.Timares,
C.Zhao,
N.Makarova,
A.V.Borovjagin,
P.L.Stewart,
H.Wu,
J.L.Blackwell,
and
D.T.Curiel
(2010).
HIV antigen incorporation within adenovirus hexon hypervariable 2 for a novel HIV vaccine approach.
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| |
PLoS One,
5,
e11815.
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R.Diskin,
P.M.Marcovecchio,
and
P.J.Bjorkman
(2010).
Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity.
|
| |
Nat Struct Mol Biol,
17,
608-613.
|
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PDB codes:
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R.Pejchal,
L.M.Walker,
R.L.Stanfield,
S.K.Phogat,
W.C.Koff,
P.Poignard,
D.R.Burton,
and
I.A.Wilson
(2010).
Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1.
|
| |
Proc Natl Acad Sci U S A,
107,
11483-11488.
|
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PDB codes:
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|
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|
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S.Gnanakaran,
M.G.Daniels,
T.Bhattacharya,
A.S.Lapedes,
A.Sethi,
M.Li,
H.Tang,
K.Greene,
H.Gao,
B.F.Haynes,
M.S.Cohen,
G.M.Shaw,
M.S.Seaman,
A.Kumar,
F.Gao,
D.C.Montefiori,
and
B.Korber
(2010).
Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.
|
| |
PLoS Comput Biol,
6,
e1000955.
|
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|
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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.
|
| |
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.
|
| |
J Pept Sci,
16,
716-722.
|
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|
|
|
|
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T.Zhou,
I.Georgiev,
X.Wu,
Z.Y.Yang,
K.Dai,
A.Finzi,
Y.D.Kwon,
J.F.Scheid,
W.Shi,
L.Xu,
Y.Yang,
J.Zhu,
M.C.Nussenzweig,
J.Sodroski,
L.Shapiro,
G.J.Nabel,
J.R.Mascola,
and
P.D.Kwong
(2010).
Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.
|
| |
Science,
329,
811-817.
|
 |
|
PDB code:
|
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|
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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.
|
| |
PLoS Pathog,
6,
e1000880.
|
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|
PDB code:
|
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|
|
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|
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W.W.Koh,
A.Forsman,
S.Hué,
G.J.van der Velden,
D.L.Yirrell,
A.McKnight,
R.A.Weiss,
and
M.M.Aasa-Chapman
(2010).
Novel subtype C human immunodeficiency virus type 1 envelopes cloned directly from plasma: coreceptor usage and neutralization phenotypes.
|
| |
J Gen Virol,
91,
2374-2380.
|
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|
|
|
|
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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.
|
| |
Proc Natl Acad Sci U S A,
107,
5972-5977.
|
 |
|
|
|
|
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A.Mor,
E.Segal,
B.Mester,
B.Arshava,
O.Rosen,
F.X.Ding,
J.Russo,
A.Dafni,
F.Schvartzman,
T.Scherf,
F.Naider,
and
J.Anglister
(2009).
Mimicking the structure of the V3 epitope bound to HIV-1 neutralizing antibodies.
|
| |
Biochemistry,
48,
3288-3303.
|
 |
|
|
|
|
 |
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.
|
| |
Chembiochem,
10,
1032-1044.
|
 |
|
|
|
|
 |
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.
|
| |
Vaccine,
27,
4672-4683.
|
 |
|
|
|
|
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D.S.Watson,
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PDB code:
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PDB codes:
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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
code is
shown on the right.
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