Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody
The malaria parasite Plasmodiumknowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human ma...
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| Format: | Article |
| Language: | English |
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PLOS ONE
2015
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| Online Access: | http://ir.unimas.my/id/eprint/8396/ http://ir.unimas.my/id/eprint/8396/1/Crystal%20Structure%20of%20Plasmodium%20knowlesi%20%28abstract%29.pdf |
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| author | Brigitte Vulliez-Le, Normand Bart, W. Faber Frederick, A. Saul Marjolein van, der Eijk Alan, W. Thomas Balbir, Singh Clemens, H. M. Kocken Graham A., Bentley |
| author_facet | Brigitte Vulliez-Le, Normand Bart, W. Faber Frederick, A. Saul Marjolein van, der Eijk Alan, W. Thomas Balbir, Singh Clemens, H. M. Kocken Graham A., Bentley |
| author_sort | Brigitte Vulliez-Le, Normand |
| building | UNIMAS Institutional Repository |
| collection | Online Access |
| description | The malaria parasite Plasmodiumknowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium merozoite invasion of the erythrocyte, is currently being pursued in human vaccine trials against P. falciparum. Recent vaccine trials in macaques using the P. knowlesi
orthologue PkAMA1 have shown that it protects against infection by this parasite species and thus should be developed for human vaccination as well. Here, we present the crystal structure
of Domains 1 and 2 of the PkAMA1 ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1. R31C2 recognizes a non-polymorphic epitope and should thus be cross-strain reactive. PkAMA1 is much less polymorphic than the
P. falciparum and P. vivax orthologues. Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host’s humoral response to AMA1. |
| first_indexed | 2025-11-15T06:22:40Z |
| format | Article |
| id | unimas-8396 |
| institution | Universiti Malaysia Sarawak |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T06:22:40Z |
| publishDate | 2015 |
| publisher | PLOS ONE |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | unimas-83962015-07-28T03:57:04Z http://ir.unimas.my/id/eprint/8396/ Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody Brigitte Vulliez-Le, Normand Bart, W. Faber Frederick, A. Saul Marjolein van, der Eijk Alan, W. Thomas Balbir, Singh Clemens, H. M. Kocken Graham A., Bentley R Medicine (General) The malaria parasite Plasmodiumknowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium merozoite invasion of the erythrocyte, is currently being pursued in human vaccine trials against P. falciparum. Recent vaccine trials in macaques using the P. knowlesi orthologue PkAMA1 have shown that it protects against infection by this parasite species and thus should be developed for human vaccination as well. Here, we present the crystal structure of Domains 1 and 2 of the PkAMA1 ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1. R31C2 recognizes a non-polymorphic epitope and should thus be cross-strain reactive. PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues. Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host’s humoral response to AMA1. PLOS ONE 2015 Article NonPeerReviewed text en http://ir.unimas.my/id/eprint/8396/1/Crystal%20Structure%20of%20Plasmodium%20knowlesi%20%28abstract%29.pdf Brigitte Vulliez-Le, Normand and Bart, W. Faber and Frederick, A. Saul and Marjolein van, der Eijk and Alan, W. Thomas and Balbir, Singh and Clemens, H. M. Kocken and Graham A., Bentley (2015) Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody. PLOS ONE, 10 (4). ISSN 1932-6203 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123567 DOI: 10.1371/journal.pone.0123567 |
| spellingShingle | R Medicine (General) Brigitte Vulliez-Le, Normand Bart, W. Faber Frederick, A. Saul Marjolein van, der Eijk Alan, W. Thomas Balbir, Singh Clemens, H. M. Kocken Graham A., Bentley Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody |
| title | Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody |
| title_full | Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody |
| title_fullStr | Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody |
| title_full_unstemmed | Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody |
| title_short | Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody |
| title_sort | crystal structure of plasmodium knowlesi apical membrane antigen 1 and its complex with an invasion-inhibitory monoclonal antibody |
| topic | R Medicine (General) |
| url | http://ir.unimas.my/id/eprint/8396/ http://ir.unimas.my/id/eprint/8396/ http://ir.unimas.my/id/eprint/8396/ http://ir.unimas.my/id/eprint/8396/1/Crystal%20Structure%20of%20Plasmodium%20knowlesi%20%28abstract%29.pdf |