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PDBsum entry 3lrs
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Immune system
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PDB id
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3lrs
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References listed in PDB file
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Key reference
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Title
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Crystal structure of pg16 and chimeric dissection with somatically related pg9: structure-Function analysis of two quaternary-Specific antibodies that effectively neutralize HIV-1.
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Authors
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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,
P.D.Kwong.
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Ref.
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J Virol, 2010,
84,
8098-8110.
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PubMed id
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Abstract
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HIV-1 resists neutralization by most antibodies. Two somatically related human
antibodies, PG9 and PG16, however, each neutralize 70-80% of circulating HIV-1
isolates. Here we present the structure of the antigen-binding fragment of PG16
in monoclinic and orthorhombic lattices at 2.4 and 4.0 A, respectively, and use
a combination of structural analysis, paratope dissection, and neutralization
assessment to determine the functional relevance of three unusual PG9/PG16
features: N-linked glycosylation, extensive affinity maturation, and a heavy
chain-third complementarity-determining region (CDR H3) that is one of the
longest observed in human antibodies. Glycosylation extended off the side of the
light chain variable domain and was not required for neutralization. The CDR H3
formed an axe-shaped subdomain, which comprised 42% of the CDR surface, with the
axe head looming approximately 20 A above the other combining loops.
Comprehensive sets of chimeric swaps between PG9 and PG16 of light chain, heavy
chain, and CDR H3 were employed to decipher structure-function relationships.
Chimeric swaps generally complemented functionally, with differences in PG9/PG16
neutralization related primarily to residue differences in CDR H3. Meanwhile,
chimeric reversions to genomic V-genes showed isolate-dependent effects with
affinity maturation playing a significant role in augmenting neutralization
breadth (p=0.037) and potency (p<0.0001). The structural and functional
details of extraordinary CDR H3 and extensive affinity maturation provide
insights into the neutralization mechanism of and the elicitation pathway for
broadly neutralizing antibodies like PG9 and PG16.
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