7z12: Difference between revisions
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The | ==VAR2 complex with PAM1.4== | ||
<StructureSection load='7z12' size='340' side='right'caption='[[7z12]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7z12]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Z12 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Z12 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3Å</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=7z12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z12 OCA], [https://pdbe.org/7z12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z12 RCSB], [https://www.ebi.ac.uk/pdbsum/7z12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z12 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A024V5I6_PLAFA A0A024V5I6_PLAFA] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria. | |||
Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA.,Raghavan SSR, Dagil R, Lopez-Perez M, Conrad J, Bassi MR, Quintana MDP, Choudhary S, Gustavsson T, Wang Y, Gourdon P, Ofori MF, Christensen SB, Minja DTR, Schmiegelow C, Nielsen MA, Barfod L, Hviid L, Salanti A, Lavstsen T, Wang K PLoS Pathog. 2022 Nov 16;18(11):e1010924. doi: 10.1371/journal.ppat.1010924. , eCollection 2022 Nov. PMID:36383559<ref>PMID:36383559</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7z12" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Plasmodium falciparum]] | |||
[[Category: Raghavan SSR]] | |||
[[Category: Wang KT]] | |||
Latest revision as of 09:58, 21 November 2024
VAR2 complex with PAM1.4VAR2 complex with PAM1.4
Structural highlights
FunctionPublication Abstract from PubMedMalaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria. Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA.,Raghavan SSR, Dagil R, Lopez-Perez M, Conrad J, Bassi MR, Quintana MDP, Choudhary S, Gustavsson T, Wang Y, Gourdon P, Ofori MF, Christensen SB, Minja DTR, Schmiegelow C, Nielsen MA, Barfod L, Hviid L, Salanti A, Lavstsen T, Wang K PLoS Pathog. 2022 Nov 16;18(11):e1010924. doi: 10.1371/journal.ppat.1010924. , eCollection 2022 Nov. PMID:36383559[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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