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Article: Conformational and structural features of HIV-1 gp120 underlying the dual receptor antagonism by cross-reactive neutralizing antibody m18

TitleConformational and structural features of HIV-1 gp120 underlying the dual receptor antagonism by cross-reactive neutralizing antibody m18
Authors
Issue Date2011
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2011, v. 50 n. 14, p. 2756-2768 How to Cite?
AbstractWe investigated the interaction between cross-reactive HIV-1 neutralizing human monoclonal antibody m18 and HIV-1 YU-2 gp120 in an effort to understand how this antibody inhibits the entry of virus into cells. m18 binds to gp120 with high affinity (K D ≈ 5 nM) as measured by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). SPR analysis further showed that m18 inhibits interactions of gp120 with both soluble CD4 and CD4-induced antibodies that have epitopes overlapping the coreceptor binding site. This dual receptor site antagonism, which occurs with equal potency for both inhibition effects, argues that m18 is not functioning as a mimic of CD4, in spite of the presence of a putative CD4-like loop formed by HCDR3 in the antibody. Consistent with this view, m18 was found to interact with gp120 in the presence of saturating concentrations of a CD4-mimicking small molecule gp120 inhibitor, suggesting that m18 does not require unoccupied CD4 Phe43 binding cavity residues of gp120. Thermodynamic analysis of the m18-gp120 interaction suggests that m18 stabilizes a conformation of gp120 that is unique from and less structured than the CD4-stabilized conformation. Conformational mutants of gp120 were studied for their impact on m18 interaction. Mutations known to disrupt the coreceptor binding region and to lead to complete suppression of 17b binding had minimal effects on m18 binding. This argues that energetically important epitopes for m18 binding lie outside the disrupted bridging sheet region used for 17b and coreceptor binding. In contrast, mutations in the CD4 region strongly affected m18 binding. Overall, the results obtained in this work argue that m18, rather than mimicking CD4 directly, suppresses both receptor binding site functions of HIV-1 gp120 by stabilizing a nonproductive conformation of the envelope protein. These results can be related to prior findings about the importance of conformational entrapment as a common mode of action for neutralizing CD4bs antibodies, with differences mainly in epitope utilization and the extent of gp120 structuring.(Figure Presented) © 2011 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/157628
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of Health (NIH)P01 GM 56550
CHAVI U19AI067854-04
NIH, National Cancer Institute, Center for Cancer Research
Funding Information:

This research was supported by National Institutes of Health (NIH) Grant P01 GM 56550 and CHAVI U19AI067854-04 and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

References

 

DC FieldValueLanguage
dc.contributor.authorGift, SKen_US
dc.contributor.authorZentner, IJen_US
dc.contributor.authorSchön, Aen_US
dc.contributor.authorMcfadden, Ken_US
dc.contributor.authorUmashankara, Men_US
dc.contributor.authorRajagopal, Sen_US
dc.contributor.authorContarino, Men_US
dc.contributor.authorDuffy, Cen_US
dc.contributor.authorCourter, JRen_US
dc.contributor.authorZhang, MYen_US
dc.contributor.authorGershoni, JMen_US
dc.contributor.authorCocklin, Sen_US
dc.contributor.authorDimitrov, DSen_US
dc.contributor.authorSmith, ABen_US
dc.contributor.authorFreire, Een_US
dc.contributor.authorChaiken, IMen_US
dc.date.accessioned2012-08-08T08:51:48Z-
dc.date.available2012-08-08T08:51:48Z-
dc.date.issued2011en_US
dc.identifier.citationBiochemistry, 2011, v. 50 n. 14, p. 2756-2768en_US
dc.identifier.issn0006-2960en_US
dc.identifier.urihttp://hdl.handle.net/10722/157628-
dc.description.abstractWe investigated the interaction between cross-reactive HIV-1 neutralizing human monoclonal antibody m18 and HIV-1 YU-2 gp120 in an effort to understand how this antibody inhibits the entry of virus into cells. m18 binds to gp120 with high affinity (K D ≈ 5 nM) as measured by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). SPR analysis further showed that m18 inhibits interactions of gp120 with both soluble CD4 and CD4-induced antibodies that have epitopes overlapping the coreceptor binding site. This dual receptor site antagonism, which occurs with equal potency for both inhibition effects, argues that m18 is not functioning as a mimic of CD4, in spite of the presence of a putative CD4-like loop formed by HCDR3 in the antibody. Consistent with this view, m18 was found to interact with gp120 in the presence of saturating concentrations of a CD4-mimicking small molecule gp120 inhibitor, suggesting that m18 does not require unoccupied CD4 Phe43 binding cavity residues of gp120. Thermodynamic analysis of the m18-gp120 interaction suggests that m18 stabilizes a conformation of gp120 that is unique from and less structured than the CD4-stabilized conformation. Conformational mutants of gp120 were studied for their impact on m18 interaction. Mutations known to disrupt the coreceptor binding region and to lead to complete suppression of 17b binding had minimal effects on m18 binding. This argues that energetically important epitopes for m18 binding lie outside the disrupted bridging sheet region used for 17b and coreceptor binding. In contrast, mutations in the CD4 region strongly affected m18 binding. Overall, the results obtained in this work argue that m18, rather than mimicking CD4 directly, suppresses both receptor binding site functions of HIV-1 gp120 by stabilizing a nonproductive conformation of the envelope protein. These results can be related to prior findings about the importance of conformational entrapment as a common mode of action for neutralizing CD4bs antibodies, with differences mainly in epitope utilization and the extent of gp120 structuring.(Figure Presented) © 2011 American Chemical Society.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_US
dc.relation.ispartofBiochemistryen_US
dc.subject.meshAntibodies, Monoclonal - Immunology - Metabolismen_US
dc.subject.meshAntibodies, Neutralizing - Immunology - Metabolismen_US
dc.subject.meshAntigens, Cd4 - Immunology - Metabolismen_US
dc.subject.meshBinding Sites - Geneticsen_US
dc.subject.meshBinding, Competitiveen_US
dc.subject.meshCalorimetryen_US
dc.subject.meshEpitopes - Immunology - Metabolismen_US
dc.subject.meshHiv Antibodies - Immunology - Metabolismen_US
dc.subject.meshHiv Envelope Protein Gp120 - Chemistry - Genetics - Metabolismen_US
dc.subject.meshHiv-1 - Immunology - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMutationen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshProtein Conformationen_US
dc.subject.meshProtein Structure, Tertiaryen_US
dc.subject.meshSurface Plasmon Resonanceen_US
dc.subject.meshThermodynamicsen_US
dc.titleConformational and structural features of HIV-1 gp120 underlying the dual receptor antagonism by cross-reactive neutralizing antibody m18en_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.doi10.1021/bi101160ren_US
dc.identifier.pmid21351734-
dc.identifier.scopuseid_2-s2.0-79953699072en_US
dc.identifier.hkuros185552-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79953699072&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume50en_US
dc.identifier.issue14en_US
dc.identifier.spage2756en_US
dc.identifier.epage2768en_US
dc.identifier.isiWOS:000289029200007-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridGift, SK=47860915200en_US
dc.identifier.scopusauthoridZentner, IJ=24170380800en_US
dc.identifier.scopusauthoridSchön, A=35489067300en_US
dc.identifier.scopusauthoridMcFadden, K=7003822811en_US
dc.identifier.scopusauthoridUmashankara, M=6506301087en_US
dc.identifier.scopusauthoridRajagopal, S=37034779200en_US
dc.identifier.scopusauthoridContarino, M=6602814352en_US
dc.identifier.scopusauthoridDuffy, C=37112073500en_US
dc.identifier.scopusauthoridCourter, JR=25631963500en_US
dc.identifier.scopusauthoridZhang, MY=35316639300en_US
dc.identifier.scopusauthoridGershoni, JM=35873146300en_US
dc.identifier.scopusauthoridCocklin, S=6507658803en_US
dc.identifier.scopusauthoridDimitrov, DS=7202564539en_US
dc.identifier.scopusauthoridSmith, AB=35429135700en_US
dc.identifier.scopusauthoridFreire, E=7103410172en_US
dc.identifier.scopusauthoridChaiken, IM=7005080392en_US

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