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Department of Energy Office of Science
GM/CA @ APS Sponsors:
National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)
 

Broadly reactive antibody neutralizes HIV-1Beta adrenergic receptors

Ian Wilson group (The Scripps Research Institute) and collaborators

 

The Wilson group collected data at GM/CA CAT to determine the structure of fragments of broadly reactive antibodies that neutralize a predominant strain of the AIDS virus, HIV-1. Developing effective HIV vaccines has proven to be extremely challenging. However, monoclonal antibodies PG9 and PG16 are extraordinarily potent and neutralize about 80% of HIV-1 clades. PG9 and PG16 target the viral envelope glycoproteins, gp120 and gp41. In both the 2.5-Å structure of the PG16 Fab , and the 3.0-Å structure of the PG6 light chain an unusual "hammerhead" sub-domain in complementarity-determining region (CDR) H3 extends from the Fab. A critical seven-residue "specificity loop" on the hammerhead sub-domain. Unexpectedly, both antibodies are sulfated at TyrH100H, and this sulfation is important for HIV neutralization. The findings provide important insights for HIV vaccine development as well as for design and engineering of antibodies for other types of therapies.

Figure: (A) overall structure of PG16 Fab, showing the CDR H3 "hammerhead" sub-domain at the top, (B) the H3 base region, (C) the H3 stalk region, and (D) full view of H3. The amino acid sequences are for the specificity loops of the two antibodies. Sulfated TyrH100H is the second Tyr in the YYDF sequence. [ Proc.Natl.Acad.Sci. USA, copyright 2010]

 

Citation:
Pejchal, R, Walker, LM, Stanfield, RL, Phogat, SK, Koff, WC, Poignard, P, Burton, DR, Wilson, IA. Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1, Proc. Natl. Acad. Sci. USA 107 (25), 11483-11488 (2010). DOI: 10.1073/pnas.1004600107


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