7n8q: Difference between revisions
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==== | ==Rhesusized RV305 DH677.3 Fab bound to Clade A/E 93TH057 HIV-1 gp120 core.== | ||
<StructureSection load='7n8q' size='340' side='right'caption='[[7n8q]]' scene=''> | <StructureSection load='7n8q' size='340' side='right'caption='[[7n8q]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7n8q]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1], [https://en.wikipedia.org/wiki/Macaca_mulatta Macaca mulatta] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N8Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N8Q FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n8q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n8q OCA], [https://pdbe.org/7n8q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n8q RCSB], [https://www.ebi.ac.uk/pdbsum/7n8q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n8q ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DPR:D-PROLINE'>DPR</scene>, <scene name='pdbligand=MPT:BETA-MERCAPTOPROPIONIC+ACID'>MPT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=U2X:O-(CYCLOHEXYLMETHYL)-L-TYROSINE'>U2X</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n8q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n8q OCA], [https://pdbe.org/7n8q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n8q RCSB], [https://www.ebi.ac.uk/pdbsum/7n8q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n8q ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A0M3KKW9_9HIV1 A0A0M3KKW9_9HIV1] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Passive transfer of monoclonal antibodies (mAbs) of human origin into Non-Human Primates (NHPs), especially those which function predominantly by a Fc-effector mechanism, requires an a priori preparation step, in which the human mAb is reengineered to an equivalent NHP IgG subclass. This can be achieved by changing both the Fc and Fab sequence while simultaneously maintaining the epitope specificity of the parent antibody. This Ab reengineering process, referred to as rhesusization, can be challenging because the simple grafting of the complementarity determining regions (CDRs) into an NHP IgG subclass may impact the functionality of the mAb. Here we describe the successful rhesusization of a set of human mAbs targeting HIV-1 envelope (Env) epitopes involved in potent Fc-effector function against the virus. This set includes a mAb targeting a linear gp120 V1V2 epitope isolated from a RV144 vaccinee, a gp120 conformational epitope within the Cluster A region isolated from a RV305 vaccinated individual, and a linear gp41 epitope within the immunodominant Cys-loop region commonly targeted by most HIV-1 infected individuals. Structural analyses confirm that the rhesusized variants bind their respective Env antigens with almost identical specificity preserving epitope footprints and most antigen-Fab atomic contacts with constant regions folded as in control RM IgG1s. In addition, functional analyses confirm preservation of the Fc effector function of the rhesusized mAbs including the ability to mediate Antibody Dependent Cell-mediated Cytotoxicity (ADCC) and antibody dependent cellular phagocytosis by monocytes (ADCP) and neutrophils (ADNP) with potencies comparable to native macaque antibodies of similar specificity. While the antibodies chosen here are relevant for the examination of the correlates of protection in HIV-1 vaccine trials, the methods used are generally applicable to antibodies for other purposes. | |||
Structure and Fc-Effector Function of Rhesusized Variants of Human Anti-HIV-1 IgG1s.,Tolbert WD, Nguyen DN, Tuyishime M, Crowley AR, Chen Y, Jha S, Goodman D, Bekker V, Mudrak SV, DeVico AL, Lewis GK, Theis JF, Pinter A, Moody MA, Easterhoff D, Wiehe K, Pollara J, Saunders KO, Tomaras GD, Ackerman M, Ferrari G, Pazgier M Front Immunol. 2022 Jan 6;12:787603. doi: 10.3389/fimmu.2021.787603. eCollection , 2021. PMID:35069563<ref>PMID:35069563</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7n8q" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
*[[Gp120 3D structures|Gp120 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human immunodeficiency virus 1]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Macaca mulatta]] | ||
[[Category: Synthetic construct]] | |||
[[Category: Pazgier M]] | |||
[[Category: Tolbert WD]] | |||
Latest revision as of 19:25, 18 October 2023
Rhesusized RV305 DH677.3 Fab bound to Clade A/E 93TH057 HIV-1 gp120 core.Rhesusized RV305 DH677.3 Fab bound to Clade A/E 93TH057 HIV-1 gp120 core.
Structural highlights
FunctionPublication Abstract from PubMedPassive transfer of monoclonal antibodies (mAbs) of human origin into Non-Human Primates (NHPs), especially those which function predominantly by a Fc-effector mechanism, requires an a priori preparation step, in which the human mAb is reengineered to an equivalent NHP IgG subclass. This can be achieved by changing both the Fc and Fab sequence while simultaneously maintaining the epitope specificity of the parent antibody. This Ab reengineering process, referred to as rhesusization, can be challenging because the simple grafting of the complementarity determining regions (CDRs) into an NHP IgG subclass may impact the functionality of the mAb. Here we describe the successful rhesusization of a set of human mAbs targeting HIV-1 envelope (Env) epitopes involved in potent Fc-effector function against the virus. This set includes a mAb targeting a linear gp120 V1V2 epitope isolated from a RV144 vaccinee, a gp120 conformational epitope within the Cluster A region isolated from a RV305 vaccinated individual, and a linear gp41 epitope within the immunodominant Cys-loop region commonly targeted by most HIV-1 infected individuals. Structural analyses confirm that the rhesusized variants bind their respective Env antigens with almost identical specificity preserving epitope footprints and most antigen-Fab atomic contacts with constant regions folded as in control RM IgG1s. In addition, functional analyses confirm preservation of the Fc effector function of the rhesusized mAbs including the ability to mediate Antibody Dependent Cell-mediated Cytotoxicity (ADCC) and antibody dependent cellular phagocytosis by monocytes (ADCP) and neutrophils (ADNP) with potencies comparable to native macaque antibodies of similar specificity. While the antibodies chosen here are relevant for the examination of the correlates of protection in HIV-1 vaccine trials, the methods used are generally applicable to antibodies for other purposes. Structure and Fc-Effector Function of Rhesusized Variants of Human Anti-HIV-1 IgG1s.,Tolbert WD, Nguyen DN, Tuyishime M, Crowley AR, Chen Y, Jha S, Goodman D, Bekker V, Mudrak SV, DeVico AL, Lewis GK, Theis JF, Pinter A, Moody MA, Easterhoff D, Wiehe K, Pollara J, Saunders KO, Tomaras GD, Ackerman M, Ferrari G, Pazgier M Front Immunol. 2022 Jan 6;12:787603. doi: 10.3389/fimmu.2021.787603. eCollection , 2021. PMID:35069563[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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