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A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120
Author(s) -
Menendez Alfredo,
Calarese Daniel A.,
Stanfield Robyn L.,
Chow Keith C.,
Scanlan Chris N.,
Kunert Renate,
Katinger Herman,
Burton Dennis R.,
Wilson Ian A.,
Scott Jamie K.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8983com
Subject(s) - epitope , chemistry , mimotope , peptide , trimer , binding site , molecular mimicry , stereochemistry , biochemistry , antibody , phage display , biology , dimer , organic chemistry , immunology
MAb 2G12 neutralizes HIV‐1 by binding with high affinity to a cluster of high‐mannose oligosac charides on the envelope glycoprotein, gp120. Screening of phage‐displayed peptide libraries with 2G12 identified peptides that bind specifically, with K d s ranging from 0.4 to 200 μM. The crystal structure of a 21‐mer peptide ligand in complex with 2G12 Fab was determined at 2.8 Å resolution. Comparison of this structure with previous structures of 2G12‐carbohydrate complexes revealed striking differences in the mechanism of 2G12 binding to peptide vs . carbohy drate. The peptide occupies a site different from, but adjacent to, the primary carbohydrate‐binding site on 2G12, and makes only slightly fewer contacts to the Fab than Man 9 GlcNAc 2 (51 vs . 56, respectively). However, only two antibody contacts with the peptide are hydro gen bonds in contrast to six with Man 9 GlcNAc 2 , and only three of the antibody residues that interact with Man 9 GlcNAc 2 also contact the peptide. Thus, this mechanism of peptide binding to 2G12 does not sup port structural mimicry of the native carbohydrate epitope on gp120, since it neither replicates the oligo saccharide footprint on the antibody nor most of the contact residues. Moreover, 2G12.1 peptide is not an immunogenic mimic of the 2G12 epitope, since anti sera produced against it did not bind gp120.—Menendez, A., Calarese, D. A., Stanfield, R. L., Chow, K. C., Scanlan, C. N., Kunert, R., Katinger, H., Burton, D. R., Wilson, I. A., Scott, J. K. A peptide inhibitor of HIV‐1 neutralizing antibody 2G12 is not a structural mimic of the natural carbohydrate epitope on gp120. FASEB J . 22, 1380–1392 (2008)