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PDBsum entry 2f5b
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Immunoglobulin
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PDB id
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2f5b
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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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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Authors
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S.Bryson,
J.P.Julien,
R.C.Hynes,
E.F.Pai.
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Ref.
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J Virol, 2009,
83,
11862-11875.
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PubMed id
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Abstract
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The quest to create a human immunodeficiency virus type 1 (HIV-1) vaccine
capable of eliciting broadly neutralizing antibodies against Env has been
challenging. Among other problems, one difficulty in creating a potent immunogen
resides in the substantial overall sequence variability of the HIV envelope
protein. The membrane-proximal region (MPER) of gp41 is a particularly conserved
tryptophan-rich region spanning residues 659 to 683, which is recognized by
three broadly neutralizing monoclonal antibodies (bnMAbs), 2F5, Z13, and 4E10.
In this study, we first describe the variability of residues in the gp41 MPER
and report on the invariant nature of 15 out of 25 amino acids comprising this
region. Subsequently, we evaluate the ability of the bnMAb 2F5 to recognize 31
varying sequences of the gp41 MPER at a molecular level. In 19 cases, resulting
crystal structures show the various MPER peptides bound to the 2F5 Fab'. A
variety of amino acid substitutions outside the 664DKW666 core epitope are
tolerated. However, changes at the 664DKW666 motif itself are restricted to
those residues that preserve the aspartate's negative charge, the hydrophobic
alkyl-pi stacking arrangement between the beta-turn lysine and tryptophan, and
the positive charge of the former. We also characterize a possible molecular
mechanism of 2F5 escape by sequence variability at position 667, which is often
observed in HIV-1 clade C isolates. Based on our results, we propose a somewhat
more flexible molecular model of epitope recognition by bnMAb 2F5, which could
guide future attempts at designing small-molecule MPER-like vaccines capable of
eliciting 2F5-like antibodies.
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