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70450171783
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note
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Two of the CD4BS antibodies were tested as full-length immunoglobulin Gs (IgGs), four as Fabs, and four in both IgG and Fab format. Neutralization by IgG and Fab for b12, b13, m18, and F105 showed similar breadths and potencies (table S1).
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21
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70450183177
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Materials and methods are available as supporting material on Science Online
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Materials and methods are available as supporting material on Science Online.
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22
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70450201766
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note
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50 for the CD4 dodecamer) (table S1) (42).
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25
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70450205567
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note
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The F105-gpl20 structure described here was solved before release of the coordinates for the unbound F105 structure (43); bound- and unbound-Fab structures, however, do closely resemble each other.
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26
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70450190445
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note
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Residue positions for antibodies are referred by Kabat numbering (44); thus, residue "100F" corresponds to insertion "F" at position "100" in Kabat nomenclature.
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27
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70450182573
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"Envelopes of approach" were assessed by comparing occluded volumes of binding ligands
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"Envelopes of approach" were assessed by comparing occluded volumes of binding ligands.
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28
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70450163392
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note
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375), which by themselves may ablate F105 binding, and so the effect of the 109-428 linkage on CD4BS antibodies had not been clearly assessed previously.
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29
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70450178980
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The percentage of gpl20-hydrophobic side chains contacted in the epitopes for antibodies b12, b13, and F105 is 27.5, 23.4, and 39.2%, respectively
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The percentage of gpl20-hydrophobic side chains contacted in the epitopes for antibodies b12, b13, and F105 is 27.5, 23.4, and 39.2%, respectively.
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30
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51349162563
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31
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70450194065
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note
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Many tier 1 HIV-1 isolates, including the BaL isolate, are neutralized by CD4BS antibodies (table S1). So whereas the F105-bound conformation of gp120 may not be favored in the functional viral spike, in tier 1 isolates, there appears to be sufficient spike flexibility to permit binding.
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32
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70450182572
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note
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CD4BS antibodies probably use a mixture of induced fit and conformational selection to bind gp120 (45). We use the term "induced" to describe the antibody-bound conformation of gp120, though "selected" might also be appropriate.
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33
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70450180489
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note
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Antibodies b12 and b13 are phage display-derived constructs. The binding of these two antibodies by their heavy chains is likely to be a direct function of this derivation, and these antibodies may not represent the expressed B cell repertoire in humans.
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34
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70450194064
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note
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A lattice interaction of convergent stems influences the position of the V1/V2 stem in the b13-gp120 crystal. Nonetheless, it is unlikely that these crystals could form, unless the structural alterations described here caused the V1/V2 stem to twist so drastically from the CD4bound state. Also, though the particular gp120 conformation recognized by b13 is a consequence in part of the gp120 alterations used in the crystallization, such alterations constrain the conformation of gp120 to be in the CD4-bound state. So the extent that these alterations affect conformation is likely to be similar to the extent that they decrease the differences between b13- and CD4-bound states.
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70450168900
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note
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368 mutant (table S8). These results, along with others that have recently been published (3-7), suggest that naturally elicited CD4BS antibodies can occur at titers sufficient to neutralize tier 2 viruses.
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44
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0004032583
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47
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70450178979
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Single-letter abbreviations for the amino acid residues are as follows; A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G., Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, GIn; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr
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Single-letter abbreviations for the amino acid residues are as follows; A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G., Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, GIn; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
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48
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70450185394
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Calculations of distances between gp120 glycans and binding surfaces of CD4 and antibodies (table S9) show that for distance cutoffs of 10 to 15 Å, the surfaces recognized by b12 and CD4 are closer to more glycans than surfaces recognized by b13 and F105
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48. Calculations of distances between gp120 glycans and binding surfaces of CD4 and antibodies (table S9) show that for distance cutoffs of 10 to 15 Å, the surfaces recognized by b12 and CD4 are closer to more glycans than surfaces recognized by b13 and F105.
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49
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70450167504
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note
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1 forms, respectively) have been deposited with the Protein Data Bank.
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