Structural and Functional Insights into the Malaria Parasite Moving Junction Complex
Publication Date
June 21, 2012
Journal
PLOS Pathogens
Authors
Brigitte Vulliez Le Normand, Michelle L. Tonkin, Mauld H. Lamarque, Susann Langer, et al
Volume
8
Issue
6
Pages
e1002755
DOI
https://dx.plos.org/10.1371/journal.ppat.1002755
Publisher URL
http://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1002755
Scopus
84864054673
Mendeley
http://www.mendeley.com/research/structural-functional-insights-malaria-parasite-moving-junction-complex
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Mendeley | Further Information

{"title"=>"Structural and functional insights into the malaria parasite moving junction complex", "type"=>"journal", "authors"=>[{"first_name"=>"Brigitte", "last_name"=>"Vulliez-Le Normand", "scopus_author_id"=>"6602689004"}, {"first_name"=>"Michelle L.", "last_name"=>"Tonkin", "scopus_author_id"=>"36464362400"}, {"first_name"=>"Mauld H.", "last_name"=>"Lamarque", "scopus_author_id"=>"6506486068"}, {"first_name"=>"Susann", "last_name"=>"Langer", "scopus_author_id"=>"55317332900"}, {"first_name"=>"Sylviane", "last_name"=>"Hoos", "scopus_author_id"=>"25822473100"}, {"first_name"=>"Magali", "last_name"=>"Roques", "scopus_author_id"=>"37054494300"}, {"first_name"=>"Frederick A.", "last_name"=>"Saul", "scopus_author_id"=>"7004357008"}, {"first_name"=>"Bart W.", "last_name"=>"Faber", "scopus_author_id"=>"8927986100"}, {"first_name"=>"Graham A.", "last_name"=>"Bentley", "scopus_author_id"=>"7103229205"}, {"first_name"=>"Martin J.", "last_name"=>"Boulanger", "scopus_author_id"=>"7004573128"}, {"first_name"=>"Maryse", "last_name"=>"Lebrun", "scopus_author_id"=>"7004811414"}], "year"=>2012, "source"=>"PLoS Pathogens", "identifiers"=>{"pmid"=>"22737069", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "doi"=>"10.1371/journal.ppat.1002755", "issn"=>"15537366", "scopus"=>"2-s2.0-84864054673", "pui"=>"365284264", "sgr"=>"84864054673"}, "id"=>"e86c542a-6e1e-3519-8ce8-cd5e30e76aea", "abstract"=>"Members of the phylum Apicomplexa, which include the malaria parasite Plasmodium, share many features in their invasion mechanism in spite of their diverse host cell specificities and life cycle characteristics. The formation of a moving junction (MJ) between the membranes of the invading apicomplexan parasite and the host cell is common to these intracellular pathogens. The MJ contains two key parasite components: the surface protein Apical Membrane Antigen 1 (AMA1) and its receptor, the Rhoptry Neck Protein (RON) complex, which is targeted to the host cell membrane during invasion. In particular, RON2, a transmembrane component of the RON complex, interacts directly with AMA1. Here, we report the crystal structure of AMA1 from Plasmodium falciparum in complex with a peptide derived from the extracellular region of PfRON2, highlighting clear specificities of the P. falciparum RON2-AMA1 interaction. The receptor-binding site of PfAMA1 comprises the hydrophobic groove and a region that becomes exposed by displacement of the flexible Domain II loop. Mutations of key contact residues of PfRON2 and PfAMA1 abrogate binding between the recombinant proteins. Although PfRON2 contacts some polymorphic residues, binding studies with PfAMA1 from different strains show that these have little effect on affinity. Moreover, we demonstrate that the PfRON2 peptide inhibits erythrocyte invasion by P. falciparum merozoites and that this strong inhibitory potency is not affected by AMA1 polymorphisms. In parallel, we have determined the crystal structure of PfAMA1 in complex with the invasion-inhibitory peptide R1 derived by phage display, revealing an unexpected structural mimicry of the PfRON2 peptide. These results identify the key residues governing the interactions between AMA1 and RON2 in P. falciparum and suggest novel approaches to antimalarial therapeutics.", "link"=>"http://www.mendeley.com/research/structural-functional-insights-malaria-parasite-moving-junction-complex", "reader_count"=>104, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>18, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>32, "Student > Postgraduate"=>6, "Student > Master"=>19, "Other"=>5, "Student > Bachelor"=>10, "Lecturer"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>18, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>32, "Student > Postgraduate"=>6, "Student > Master"=>19, "Other"=>5, "Student > Bachelor"=>10, "Lecturer"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>13, "Agricultural and Biological Sciences"=>65, "Medicine and Dentistry"=>7, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>1, "Chemistry"=>6, "Computer Science"=>2, "Immunology and Microbiology"=>5}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Chemistry"=>{"Chemistry"=>6}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>65}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>13}, "Unspecified"=>{"Unspecified"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Kenya"=>1, "Indonesia"=>1, "India"=>2}, "group_count"=>2}

CrossRef

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/620842"], "description"=>"<p>(A) Top (left) and end-on (right) views of <i>Pf</i>AMA1-<i>Pf</i>RON2sp1 (orange cartoon) overlayed on <i>Pf</i>AMA1-R1-major (yellow)/R1-minor (purple), show that the <i>Pf</i>AMA1 groove is capable of accepting only <i>Pf</i>RON2sp1 or the two R1 peptides at one time. Box 1 shows that Phe-P5 of R1 mimics Phe367 of the DII loop, while boxes 2 and 3 highlight spatial conservation of a phenylalanine anchor at the center of the groove, and a knob-in-hole interaction incorporating the peptide Arg-P15. R1-major is shown in yellow, <i>Pf</i>RON2sp1 in orange and apo PfAMA1 in green. (B). Comparison of the R1 and <i>Pf</i>RON2sp1 sequences reveals five identical (red) and two similar (blue) residues.</p>", "links"=>[], "tags"=>["mimicry", "peptide", "r1", "binding"], "article_id"=>291330, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g004", "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_mimicry_of_Pf_RON2_by_peptide_R1_in_binding_to_Pf_AMA1_/291330", "title"=>"Structural mimicry of <i>Pf</i>RON2 by peptide R1 in binding to <i>Pf</i>AMA1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:22:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/621523"], "description"=>"<p>Independent experiments were performed at least three times and the values represent the mean ± SD.</p>", "links"=>[], "tags"=>["equilibrium", "dissociation", "constants", "binding", "peptides", "ama1", "strains"], "article_id"=>292003, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.t001", "stats"=>{"downloads"=>7, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Apparent_equilibrium_dissociation_constants_K_D_nM_for_the_binding_of_peptides_Pf_RON2sp1_and_Pf_RON2sp2_to_AMA1_from_different_strains_of_P_falciparum_/292003", "title"=>"Apparent equilibrium dissociation constants K<sub>D</sub> (nM) for the binding of peptides <i>Pf</i>RON2sp1 and <i>Pf</i>RON2sp2 to AMA1 from different strains of <i>P. falciparum</i>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-06-21 00:33:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/621484"], "description"=>"<p>Values in parenthesis are for the last resolution shell.</p>", "links"=>[], "tags"=>["refinement"], "article_id"=>291972, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.t002", "stats"=>{"downloads"=>1, "page_views"=>40, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Crystallographic_parameters_data_collection_statistics_and_refinement_summary_/291972", "title"=>"Crystallographic parameters, data collection statistics and refinement summary.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-06-21 00:32:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/621019"], "description"=>"<p>(A). Left - sensorgrams, showing R1 (analyte) binding to <i>Pf</i>AMA1 3D7mut (immobilized). R1 concentrations are indicated for each curve (µM). Right - the variation in percentage of bound sites (deduced from the steady-state response) with respect to analyte concentration. (B). Left - sensorgrams, showing R1 (analyte) binding to Dico3 (immobilized), with R1 concentrations indicated. Right - the variation in percentage of bound sites (deduced from the steady-state response) with respect to analyte concentration. The equilibrium dissociation constant K<sub>D</sub> derived from the steady state binding curves is 15.2 µM for 3D7mut and 22.3 µM for Dico3.</p>", "links"=>[], "tags"=>["plasmon", "resonance", "studies", "peptide", "r1", "binding", "mutants", "3d7mut"], "article_id"=>291495, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g006", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Surface_Plasmon_Resonance_studies_of_peptide_R1_binding_to_Pf_AMA1_mutants_3D7mut_and_Dico3_/291495", "title"=>"Surface Plasmon Resonance studies of peptide R1 binding to <i>Pf</i>AMA1 mutants 3D7mut and Dico3.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:24:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/621233"], "description"=>"<p>(A). Alignment of RON2 sequences truncated to correlate <i>Pf</i>RON2sp1 with RON2 sequences from the following accession numbers: <i>Tg</i>RON2 - TGME49_100100, <i>Nc</i>RON2 - NCLIV_064620, <i>Pf</i>RON2 - PF14_0495, <i>Pv</i>RON2 - PVX_117880, <i>Py</i>RON2 – PY_06813, <i>Bb</i>RON2 (BBOV_I001630). (B). Overlay of <i>Tg</i>RON2sp (green; PDB ID 2Y8T) onto <i>Pf</i>AMA1-<i>Pf</i>RON2sp (blue-orange) shows that both peptides adopt a helix/coil/cystine loop/coil architecture in the AMA1 groove, with the highest divergence localized to the cystine loop (black arrow). (C). Electrostatic surface renderings of <i>Pf</i>AMA1 (left) and <i>Tg</i>AMA1 (right), with the secondary structure of the RON2 binding partner and residues defining the base of cystine loop shown, illustrates that both interactions are highly complementary, but highly genus specific.</p>", "links"=>[], "tags"=>["ron2", "cystine", "governs"], "article_id"=>291721, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g008", "stats"=>{"downloads"=>2, "page_views"=>74, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_RON2_cystine_loop_governs_specificity_/291721", "title"=>"The RON2 cystine loop governs specificity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:28:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/621333"], "description"=>"<p>(A). Left - A cut-away surface of <i>Pf</i>AMA1 (blue), reveals that Arg2041 of <i>Pf</i>RON2sp1 (orange) integrates deeply into a well-defined pocket. Right - However, no analogous pocket is observed in <i>Pv</i>AMA1 (grey; PDB ID 1W8K). (B). Peptides and antibodies known to be invasion inhibitory for <i>P. falciparum</i> occupy the key Arg binding site, as shown by orthogonal views of the <i>Pf</i>AMA1-<i>Pf</i>RON2sp1 co-structure (blue-orange) overlayed with the mAb 1F9 co-structure (1F9, green; PDB ID 2Q8B), IgNAR14l-1 co-structure (IgNAR, purple; PDB ID 2Z8V), and R1 co-structure (R1, yellow; reported here).</p>", "links"=>[], "tags"=>["arg", "knob-in-hole", "selectivity", "inhibitory", "antibodies"], "article_id"=>291818, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g009", "stats"=>{"downloads"=>5, "page_views"=>120, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Arg_knob_in_hole_interaction_is_critical_for_species_selectivity_and_interaction_with_invasion_inhibitory_antibodies_and_peptides_/291818", "title"=>"The Arg knob-in-hole interaction is critical for species selectivity and interaction with invasion inhibitory antibodies and peptides.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:30:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/620474"], "description"=>"<p>(A) <i>Pf</i>RON2sp1 (orange) and <i>Pf</i>RON2sp2 (grey) represent peptides of <i>Pf</i>RON2 (green). SP, signal peptide. TMD, putative transmembrane domain. (B). Sensorgrams showing <i>Pf</i>RON2sp1 (analyte) binding to <i>Pf</i>AMA1 3D7 (immobilized). The <i>Pf</i>RON2sp1 concentrations are indicated for each curve (nM). (C). Sensorgrams showing <i>Pf</i>RON2sp2 (analyte) binding to <i>Pf</i>AMA1 CAMP (immobilized), with <i>Pf</i>RON2sp2 concentrations indicated. (D, E). Variation percentage of bound sites (deduced from the steady-state response) with respect to analyte concentration (D, <i>Pf</i>RON2sp1; E, <i>Pf</i>RON2sp2) obtained from binding to immobilized recombinant <i>Pf</i>AMA1 from strains 3D7 (shown in B), CAMP (shown in C), FVO and HB3. The derived apparent equilibrium dissociation constants K<sub>D</sub> are given in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002755#ppat-1002755-t001\" target=\"_blank\">Table 1</a>.</p>", "links"=>[], "tags"=>["plasmon", "resonance", "studies", "peptides", "binding", "recombinant", "strains", "higher"], "article_id"=>290951, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Surface_Plasmon_Resonance_studies_of_peptides_Pf_RON2sp1_and_Pf_RON2sp2_binding_to_recombinant_Pf_AMA1_from_multiple_strains_reveal_that_Pf_RON2sp1_has_a_consistently_higher_affinity_/290951", "title"=>"Surface Plasmon Resonance studies of peptides <i>Pf</i>RON2sp1 and <i>Pf</i>RON2sp2 binding to recombinant <i>Pf</i>AMA1 from multiple strains reveal that <i>Pf</i>RON2sp1 has a consistently higher affinity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:15:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/322340", "https://ndownloader.figshare.com/files/322406", "https://ndownloader.figshare.com/files/322504", "https://ndownloader.figshare.com/files/322620", "https://ndownloader.figshare.com/files/322680"], "description"=>"<div><p>Members of the phylum Apicomplexa, which include the malaria parasite <em>Plasmodium</em>, share many features in their invasion mechanism in spite of their diverse host cell specificities and life cycle characteristics. The formation of a moving junction (MJ) between the membranes of the invading apicomplexan parasite and the host cell is common to these intracellular pathogens. The MJ contains two key parasite components: the surface protein Apical Membrane Antigen 1 (AMA1) and its receptor, the Rhoptry Neck Protein (RON) complex, which is targeted to the host cell membrane during invasion. In particular, RON2, a transmembrane component of the RON complex, interacts directly with AMA1. Here, we report the crystal structure of AMA1 from <em>Plasmodium falciparum</em> in complex with a peptide derived from the extracellular region of <em>Pf</em>RON2, highlighting clear specificities of the <em>P. falciparum</em> RON2-AMA1 interaction. The receptor-binding site of <em>Pf</em>AMA1 comprises the hydrophobic groove and a region that becomes exposed by displacement of the flexible Domain II loop. Mutations of key contact residues of <em>Pf</em>RON2 and <em>Pf</em>AMA1 abrogate binding between the recombinant proteins. Although <em>Pf</em>RON2 contacts some polymorphic residues, binding studies with <em>Pf</em>AMA1 from different strains show that these have little effect on affinity. Moreover, we demonstrate that the <em>Pf</em>RON2 peptide inhibits erythrocyte invasion by <em>P. falciparum</em> merozoites and that this strong inhibitory potency is not affected by AMA1 polymorphisms. In parallel, we have determined the crystal structure of <em>Pf</em>AMA1 in complex with the invasion-inhibitory peptide R1 derived by phage display, revealing an unexpected structural mimicry of the <em>Pf</em>RON2 peptide. These results identify the key residues governing the interactions between AMA1 and RON2 in <em>P. falciparum</em> and suggest novel approaches to antimalarial therapeutics.</p> </div>", "links"=>[], "tags"=>["insights", "malaria", "parasite", "moving", "junction"], "article_id"=>123628, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002755.s001", "https://dx.doi.org/10.1371/journal.ppat.1002755.s002", "https://dx.doi.org/10.1371/journal.ppat.1002755.s003", "https://dx.doi.org/10.1371/journal.ppat.1002755.s004", "https://dx.doi.org/10.1371/journal.ppat.1002755.s005"], "stats"=>{"downloads"=>9, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Structural_and_Functional_Insights_into_the_Malaria_Parasite_Moving_Junction_Complex/123628", "title"=>"Structural and Functional Insights into the Malaria Parasite Moving Junction Complex", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-06-21 01:00:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/621108"], "description"=>"<p>(A) Interface between <i>Pf</i>AMA1 and <i>Pf</i>RON2sp1 shown in open-book presentation. Residues of both components that were mutated are labeled. (B). Binding characteristics of recombinant GST-<i>Pf</i>RON2-5 mutants to dissect hot-spot residues in <i>Pf</i>RON2. <i>Pf</i>AMA1-expressing BHK-21 cells were incubated with 10 µg/ml of <i>Pf</i>RON2 or mutated proteins (GST-fusion proteins), washed and the binding of recombinant <i>Pf</i>RON2 fragment was revealed with anti-GST antibody. <i>Pf</i>AMA1 was detected with mAb F8.12.19, which recognizes extracellular Domain III. (C). Binding consequences of <i>Pf</i>AMA1 mutations. Mutated versions of <i>Pf</i>AMA1 were expressed on the surface of BHK-21 cells and incubated with wild-type <i>Pf</i>RON2 recombinant proteins at 10 and 1 µg/ml.</p>", "links"=>[], "tags"=>["residues", "affinity"], "article_id"=>291599, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g007", "stats"=>{"downloads"=>3, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mutations_of_Pf_AMA1_and_Pf_RON2_5_reveal_residues_critical_for_high_affinity_interaction_/291599", "title"=>"Mutations of <i>Pf</i>AMA1 and <i>Pf</i>RON2-5 reveal residues critical for high affinity interaction.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:26:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/620961"], "description"=>"<p>Comparison of <i>Pf</i>RON2sp1 and R1 peptides (concentrations 0.2 to 20 µM) in inhibiting red blood cell invasion by <i>P. falciparum</i> 3D7 or HB3 highlights the higher inhibitory efficiency and cross-strain reactivity of <i>Pf</i>RON2sp1. Parasitemia of control infected red blood cells (IRBC) 16 hours post-invasion was used as the 100% invasion reference. Means (± SD for N = 3) are shown.</p>", "links"=>[], "tags"=>["potent", "cross-strain", "inhibition"], "article_id"=>291444, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g005", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Highly_potent_cross_strain_inhibition_of_red_blood_cell_invasion_of_Pf_RON2sp1_/291444", "title"=>"Highly potent cross-strain inhibition of red blood cell invasion of <i>Pf</i>RON2sp1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:24:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/620704"], "description"=>"<p>(A). The co-crystal structure of <i>Pf</i>AMA1 (blue surface) with R1 reveals two bound peptides, R1 major (yellow) and R1 minor (purple). (B). Detailed analysis of interactions at the <i>Pf</i>AMA1–R1-major, <i>Pf</i>AMA1–R1-minor, and R1-major–R1-minor interfaces. Surface representation of <i>Pf</i>AMA1 (blue), with R1-major (yellow) and R1-minor (purple) shown as cartoons. Box 1 – R1-major anchors its N-terminus to <i>Pf</i>AMA1 through 3 backbone hydrogen bonds. Box 2 – the central region of the <i>Pf</i>AMA1 apical groove is occupied by R1-major through both hydrophobic and polar interactions. Box 3 – R1-minor forms most of its anchor points to <i>Pf</i>AMA1 through the apical loops and does not contact the base of the groove, which is occupied by R1-major. Panel 4 – Backbone hydrogen bonds between R1-minor and R1-major generate a β-sheet, while R1-major is further pinned to the <i>Pf</i>AMA1 groove through 3 hydrogen bonds. Panel 5 – R1-major integrates into <i>Pf</i>AMA1 with the use of an arginine knob-in-hole interaction stabilized by 6 hydrogen bonds, which is also exploited by<i>Pf</i>RON2sp.</p>", "links"=>[], "tags"=>["complexed", "r1"], "article_id"=>291191, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g003", "stats"=>{"downloads"=>3, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structure_of_Pf_AMA1_complexed_with_R1_peptide_/291191", "title"=>"Structure of <i>Pf</i>AMA1 complexed with R1 peptide.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:19:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/620584"], "description"=>"<p>(A) Top - Co-crystal structures of <i>Pf</i>AMA1 (blue surface) with <i>Pf</i>RON2sp1 (orange) and <i>Pf</i>RON2sp2 (grey), show a disulfide-anchored U-shaped conformation in the apical groove of <i>Pf</i>AMA1. Bottom - Electron density map (orange) for <i>Pf</i>RON2sp1 contoured at 1.0 σ, highlighting well ordered density from the N-terminal helix, through the cystine loop, to the C-terminal coil. (B) Notable changes in the structure of <i>Pf</i>AMA1 between the apo structure (green; PDB ID 1Z40) and the <i>Pf</i>AMA1-<i>Pf</i>RON2sp1 co-structure (blue-orange) as observed from a side view. Box 1 - The DII loop of apo <i>Pf</i>AMA1 is ejected from the apical groove during binding to <i>Pf</i>RON2sp1, leaving room for the <i>Pf</i>RON2sp1 N-terminal helix to occupy the space vacated by the DII loop helix. Box 2 - The β-strands of the <i>Pf</i>RON2sp1 cystine loop order a <i>Pf</i>AMA1 surface loop, generating a contiguous three-stranded β-sheet. (C) In the region of the <i>Pf</i>RON2sp1 N-terminal helix, there is notable structural mimicry to the <i>Pf</i>AMA1 apo DII loop, including several conserved residues, and a conserved hydrogen bonding network incorporating three buried water molecules. (D) Arg2041, specific to <i>P. falciparum</i>, fits snugly into a deep pocket in the surface of <i>Pf</i>AMA1 and is stabilized through a complex network of seven hydrogen bonds.</p>", "links"=>[], "tags"=>["complexed"], "article_id"=>291068, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.g002", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structure_of_Pf_AMA1_complexed_with_Pf_RON2_derived_peptides_/291068", "title"=>"Structure of <i>Pf</i>AMA1 complexed with <i>Pf</i>RON2-derived peptides.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-21 00:17:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/621448"], "description"=>"<p>Refinement statistics.</p>", "links"=>[], "tags"=>["microbiology", "Biochemistry"], "article_id"=>291934, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Brigitte Vulliez-Le Normand", "Michelle L. Tonkin", "Mauld H. Lamarque", "Susann Langer", "Sylviane Hoos", "Magali Roques", "Frederick A. Saul", "Bart W. Faber", "Graham A. Bentley", "Martin J. Boulanger", "Maryse Lebrun"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002755.t003", "stats"=>{"downloads"=>1, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Refinement_statistics_/291934", "title"=>"Refinement statistics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-06-21 00:32:14"}

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