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PDBsum entry 3mug
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Immune system
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PDB id
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3mug
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Contents |
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(+ 0 more)
212 a.a.
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(+ 0 more)
239 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure and function of broadly reactive antibody pg16 reveal an h3 subdomain that mediates potent neutralization of HIV-1.
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Authors
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R.Pejchal,
L.M.Walker,
R.L.Stanfield,
S.K.Phogat,
W.C.Koff,
P.Poignard,
D.R.Burton,
I.A.Wilson.
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Ref.
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Proc Natl Acad Sci U S A, 2010,
107,
11483-11488.
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PubMed id
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Abstract
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Development of an effective vaccine against HIV-1 will likely require
elicitation of broad and potent neutralizing antibodies against the trimeric
surface envelope glycoprotein (Env). Monoclonal antibodies (mAbs) PG9 and PG16
neutralize approximately 80% of HIV-1 isolates across all clades with
extraordinary potency and target novel epitopes preferentially expressed on Env
trimers. As these neutralization properties are ideal for a vaccine-elicited
antibody response to HIV-1, their structural basis was investigated. The crystal
structure of the antigen-binding fragment (Fab) of PG16 at 2.5 A resolution
revealed its unusually long, 28-residue, complementarity determining region
(CDR) H3 forms a unique, stable subdomain that towers above the antibody
surface. A 7-residue "specificity loop" on the "hammerhead" subdomain was
identified that, when transplanted from PG16 to PG9 and vice versa, accounted
for differences in the fine specificity and neutralization of these two mAbs.
The PG16 electron density maps also revealed that a CDR H3 tyrosine was
sulfated, which was confirmed for both PG9 (doubly) and PG16 (singly) by mass
spectral analysis. We further showed that tyrosine sulfation plays a role in
binding and neutralization. An N-linked glycan modification is observed in the
variable light chain, but not required for antigen recognition. Further, the
crystal structure of the PG9 light chain at 3.0 A facilitated homology modeling
to support the presence of these unusual features in PG9. Thus, PG9 and PG16 use
unique structural features to mediate potent neutralization of HIV-1 that may be
of utility in antibody engineering and for high-affinity recognition of a
variety of therapeutic targets.
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