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Article: Structural mimicry of CD4 by a cross-reactive HIV-1 neutralizing antibody with CDR-H2 and H3 containing unique motifs

TitleStructural mimicry of CD4 by a cross-reactive HIV-1 neutralizing antibody with CDR-H2 and H3 containing unique motifs
Authors
Issue Date2006
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmb
Citation
Journal Of Molecular Biology, 2006, v. 357 n. 1, p. 82-99 How to Cite?
AbstractHuman 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 Å 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 Å long and rigid, forming an extended β-sheet decorated with an α-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.
Persistent Identifierhttp://hdl.handle.net/10722/157440
ISSN
2015 Impact Factor: 4.517
2015 SCImago Journal Rankings: 3.002
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorPrabakaran, Pen_US
dc.contributor.authorGan, Jen_US
dc.contributor.authorWu, YQen_US
dc.contributor.authorZhang, MYen_US
dc.contributor.authorDimitrov, DSen_US
dc.contributor.authorJi, Xen_US
dc.date.accessioned2012-08-08T08:49:59Z-
dc.date.available2012-08-08T08:49:59Z-
dc.date.issued2006en_US
dc.identifier.citationJournal Of Molecular Biology, 2006, v. 357 n. 1, p. 82-99en_US
dc.identifier.issn0022-2836en_US
dc.identifier.urihttp://hdl.handle.net/10722/157440-
dc.description.abstractHuman 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 Å 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 Å long and rigid, forming an extended β-sheet decorated with an α-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.en_US
dc.languageengen_US
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmben_US
dc.relation.ispartofJournal of Molecular Biologyen_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshAntibodies, Monoclonal - Chemistry - Genetics - Immunologyen_US
dc.subject.meshAntigens, Cd4 - Chemistry - Immunologyen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshComplementarity Determining Regionsen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshEpitopesen_US
dc.subject.meshHiv Antibodies - Chemistry - Genetics - Immunologyen_US
dc.subject.meshHiv Envelope Protein Gp120 - Chemistry - Metabolismen_US
dc.subject.meshHiv-1 - Immunologyen_US
dc.subject.meshHumansen_US
dc.subject.meshHydrogen Bondingen_US
dc.subject.meshImmunoglobulin Fab Fragments - Chemistry - Genetics - Immunologyen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMolecular Mimicryen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshProtein Structure, Secondaryen_US
dc.subject.meshProtein Structure, Tertiaryen_US
dc.subject.meshSequence Alignmenten_US
dc.titleStructural mimicry of CD4 by a cross-reactive HIV-1 neutralizing antibody with CDR-H2 and H3 containing unique motifsen_US
dc.typeArticleen_US
dc.identifier.emailZhang, MY:zhangmy@hku.hken_US
dc.identifier.authorityZhang, MY=rp01409en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.jmb.2005.12.062en_US
dc.identifier.pmid16426633-
dc.identifier.scopuseid_2-s2.0-33644768318en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33644768318&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume357en_US
dc.identifier.issue1en_US
dc.identifier.spage82en_US
dc.identifier.epage99en_US
dc.identifier.isiWOS:000235823900008-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridPrabakaran, P=6603634046en_US
dc.identifier.scopusauthoridGan, J=35363944800en_US
dc.identifier.scopusauthoridWu, YQ=12767279700en_US
dc.identifier.scopusauthoridZhang, MY=35316639300en_US
dc.identifier.scopusauthoridDimitrov, DS=7202564539en_US
dc.identifier.scopusauthoridJi, X=7402840134en_US

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