2aj3
From Proteopedia
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| - | [[Image:2aj3.gif|left|200px]]<br /> | + | [[Image:2aj3.gif|left|200px]]<br /><applet load="2aj3" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2aj3" size=" | + | |
caption="2aj3, resolution 2.03Å" /> | caption="2aj3, resolution 2.03Å" /> | ||
'''Crystal Structure of a Cross-Reactive HIV-1 Neutralizing CD4-Binding Site Antibody Fab m18'''<br /> | '''Crystal Structure of a Cross-Reactive HIV-1 Neutralizing CD4-Binding Site Antibody Fab m18'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Human immunodeficiency virus (HIV) entry into cells is initiated by the | + | Human immunodeficiency virus (HIV) entry into cells is initiated by the binding of its envelope glycoprotein (Env) gp120 to receptor CD4. Antibodies that bind to epitopes overlapping the CD4-binding site (CD4bs) on gp120 can prevent HIV entry by competing with cell-associated CD4; their ability to outcompete CD4 is a major determinant of their neutralizing potency and is proportional to their avidity. The breadth of neutralization and the likelihood of the emergence of antibody-resistant virus are critically dependent on the structure of their epitopes. Because CD4bs is highly conserved, it is reasonable to hypothesize that antibodies closely mimicking CD4 could exhibit relatively broad cross-reactivity and a high probability of preventing the emergence of resistant viruses. Previously, in a search for antibodies that mimic CD4 or the co-receptor, we identified and characterized a broadly cross-reactive HIV-neutralizing CD4bs human monoclonal antibody (hmAb), m18. Here, we describe the crystal structure of Fab m18 at 2.03 A resolution, which reveals unique conformations of heavy chain complementarity-determining regions (CDRs) 2 and 3 (H2 and H3). H2 is highly bulged and lacks cross-linking interstrand hydrogen bonds observed in all four canonical structures. H3 is 17.5 A long and rigid, forming an extended beta-sheet decorated with an alpha-turn motif bearing a phenylalanine-isoleucine fork at the apex. It shows striking similarity to the Ig CDR2-like C'C'' region of the CD4 first domain D1 that dominates the binding of CD4 to gp120. Docking simulations suggest significant similarity between the m18 epitope and the CD4bs on gp120. Fab m18 does not enhance binding of CD4-induced (CD4i) antibodies, nor does it induce CD4-independent fusion mediated by the HIV Env. Thus, vaccine immunogens based on the m18 epitope structure are unlikely to elicit antibodies that could enhance infection. The structure can also serve as a basis for the design of novel, highly efficient inhibitors of HIV entry. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2AJ3 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 2AJ3 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AJ3 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Dimitrov, D | + | [[Category: Dimitrov, D S.]] |
[[Category: Gan, J.]] | [[Category: Gan, J.]] | ||
[[Category: Ji, X.]] | [[Category: Ji, X.]] | ||
[[Category: Prabakaran, P.]] | [[Category: Prabakaran, P.]] | ||
| - | [[Category: Wu, Y | + | [[Category: Wu, Y Q.]] |
| - | [[Category: Zhang, M | + | [[Category: Zhang, M Y.]] |
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: antibody]] | [[Category: antibody]] | ||
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[[Category: immunoglobulin]] | [[Category: immunoglobulin]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:27:54 2008'' |
Revision as of 14:27, 21 February 2008
|
Crystal Structure of a Cross-Reactive HIV-1 Neutralizing CD4-Binding Site Antibody Fab m18
Contents |
Overview
Human immunodeficiency virus (HIV) entry into cells is initiated by the binding of its envelope glycoprotein (Env) gp120 to receptor CD4. Antibodies that bind to epitopes overlapping the CD4-binding site (CD4bs) on gp120 can prevent HIV entry by competing with cell-associated CD4; their ability to outcompete CD4 is a major determinant of their neutralizing potency and is proportional to their avidity. The breadth of neutralization and the likelihood of the emergence of antibody-resistant virus are critically dependent on the structure of their epitopes. Because CD4bs is highly conserved, it is reasonable to hypothesize that antibodies closely mimicking CD4 could exhibit relatively broad cross-reactivity and a high probability of preventing the emergence of resistant viruses. Previously, in a search for antibodies that mimic CD4 or the co-receptor, we identified and characterized a broadly cross-reactive HIV-neutralizing CD4bs human monoclonal antibody (hmAb), m18. Here, we describe the crystal structure of Fab m18 at 2.03 A resolution, which reveals unique conformations of heavy chain complementarity-determining regions (CDRs) 2 and 3 (H2 and H3). H2 is highly bulged and lacks cross-linking interstrand hydrogen bonds observed in all four canonical structures. H3 is 17.5 A long and rigid, forming an extended beta-sheet decorated with an alpha-turn motif bearing a phenylalanine-isoleucine fork at the apex. It shows striking similarity to the Ig CDR2-like C'C region of the CD4 first domain D1 that dominates the binding of CD4 to gp120. Docking simulations suggest significant similarity between the m18 epitope and the CD4bs on gp120. Fab m18 does not enhance binding of CD4-induced (CD4i) antibodies, nor does it induce CD4-independent fusion mediated by the HIV Env. Thus, vaccine immunogens based on the m18 epitope structure are unlikely to elicit antibodies that could enhance infection. The structure can also serve as a basis for the design of novel, highly efficient inhibitors of HIV entry.
Disease
Known disease associated with this structure: Kappa light chain deficiency OMIM:[147200]
About this Structure
2AJ3 is a Protein complex structure of sequences from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Structural mimicry of CD4 by a cross-reactive HIV-1 neutralizing antibody with CDR-H2 and H3 containing unique motifs., Prabakaran P, Gan J, Wu YQ, Zhang MY, Dimitrov DS, Ji X, J Mol Biol. 2006 Mar 17;357(1):82-99. Epub 2006 Jan 9. PMID:16426633
Page seeded by OCA on Thu Feb 21 16:27:54 2008
Categories: Homo sapiens | Protein complex | Dimitrov, D S. | Gan, J. | Ji, X. | Prabakaran, P. | Wu, Y Q. | Zhang, M Y. | SO4 | Antibody | Cd4-binding | Fab | Hiv | Immunoglobulin
