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PDBsum entry 4jkp
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Viral protein/immune system
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PDB id
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4jkp
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Contents |
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340 a.a.
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222 a.a.
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207 a.a.
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PDB id:
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| Name: |
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Viral protein/immune system
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Title:
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Restricting HIV-1 pathways for escape using rationally-designed anti- HIV-1 antibodies
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Structure:
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Gp120. Chain: g. Engineered: yes. Heavy chain of antibody 45-46m2. Chain: h. Engineered: yes. Light chain of antibody 45-46m2. Chain: l. Engineered: yes
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Source:
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Human immunodeficiency virus 1. HIV. Organism_taxid: 11676. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Homo sapiens. Human. Organism_taxid: 9606. Expressed in: homo sapiens.
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Resolution:
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2.82Å
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R-factor:
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0.195
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R-free:
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0.231
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Authors:
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R.Diskin,P.J.Bjorkman
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Key ref:
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R.Diskin
et al.
(2013).
Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies.
J Exp Med,
210,
1235-1249.
PubMed id:
DOI:
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Date:
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11-Mar-13
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Release date:
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15-May-13
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PROCHECK
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Headers
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References
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Q0ED31
(Q0ED31_HV1) -
Envelope glycoprotein gp160 from Human immunodeficiency virus type 1
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Seq:
Struc:
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857 a.a.
340 a.a.*
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DOI no:
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J Exp Med
210:1235-1249
(2013)
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PubMed id:
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Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies.
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R.Diskin,
F.Klein,
J.A.Horwitz,
A.Halper-Stromberg,
D.N.Sather,
P.M.Marcovecchio,
T.Lee,
A.P.West,
H.Gao,
M.S.Seaman,
L.Stamatatos,
M.C.Nussenzweig,
P.J.Bjorkman.
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ABSTRACT
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Recently identified broadly neutralizing antibodies (bNAbs) that potently
neutralize most HIV-1 strains are key to potential antibody-based therapeutic
approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing
bNAb potencies and resistance to common routes of HIV-1 escape through mutation
would facilitate their use as therapeutics. We previously used structure-based
design to create the bNAb NIH45-46(G54W), which exhibits superior potency and/or
breadth compared with other bNAbs. We report new, more effective NIH45-46(G54W)
variants designed using analyses of the NIH45-46-gp120 complex structure and
sequences of NIH45-46(G54W)-resistant HIV-1 strains. One variant, 45-46m2,
neutralizes 96% of HIV-1 strains in a cross-clade panel and viruses isolated
from an HIV-infected individual that are resistant to all other known bNAbs,
making it the single most broad and potent anti-HIV-1 antibody to date. A
description of its mechanism is presented based on a 45-46m2-gp120 crystal
structure. A second variant, 45-46m7, designed to thwart HIV-1 resistance to
NIH45-46(G54W) arising from mutations in a gp120 consensus sequence, targets a
common route of HIV-1 escape. In combination, 45-46m2 and 45-46m7 reduce the
possible routes for the evolution of fit viral escape mutants in
HIV-1YU-2-infected humanized mice, with viremic control exhibited when a third
antibody, 10-1074, was added to the combination.
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Links
