Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase
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{"title"=>"Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase", "type"=>"journal", "authors"=>[{"first_name"=>"Eva", "last_name"=>"Kowalinski", "scopus_author_id"=>"24512267200"}, {"first_name"=>"Chloe", "last_name"=>"Zubieta", "scopus_author_id"=>"6603203329"}, {"first_name"=>"Andrea", "last_name"=>"Wolkerstorfer", "scopus_author_id"=>"26636174200"}, {"first_name"=>"Oliver H.J.", "last_name"=>"Szolar", "scopus_author_id"=>"57194812032"}, {"first_name"=>"Rob W.H.", "last_name"=>"Ruigrok", "scopus_author_id"=>"7004672634"}, {"first_name"=>"Stephen", "last_name"=>"Cusack", "scopus_author_id"=>"7006566433"}], "year"=>2012, "source"=>"PLoS Pathogens", "identifiers"=>{"scopus"=>"2-s2.0-84866177810", "sgr"=>"84866177810", "issn"=>"15537366", "doi"=>"10.1371/journal.ppat.1002831", "pmid"=>"22876177", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "pui"=>"365631410"}, "id"=>"f15ac0db-70df-3a8c-9938-c34695215f69", "abstract"=>"It is generally recognised that novel antiviral drugs, less prone to resistance, would be a desirable alternative to current drug options in order to be able to treat potentially serious influenza infections. The viral polymerase, which performs transcription and replication of the RNA genome, is an attractive target for antiviral drugs since potent polymerase inhibitors could directly stop viral replication at an early stage. Recent structural studies on functional domains of the heterotrimeric polymerase, which comprises subunits PA, PB1 and PB2, open the way to a structure based approach to optimise inhibitors of viral replication. In particular, the unique cap-snatching mechanism of viral transcription can be inhibited by targeting either the PB2 cap-binding or PA endonuclease domains. Here we describe high resolution X-ray co-crystal structures of the 2009 pandemic H1N1 (pH1N1) PA endonuclease domain with a series of specific inhibitors, including four diketo compounds and a green tea catechin, all of which chelate the two critical manganese ions in the active site of the enzyme. Comparison of the binding mode of the different compounds and that of a mononucleotide phosphate highlights, firstly, how different substituent groups on the basic metal binding scaffold can be orientated to bind in distinct sub-pockets within the active site cavity, and secondly, the plasticity of certain structural elements of the active site cavity, which result in induced fit binding. These results will be important in optimising the design of more potent inhibitors targeting the cap-snatching endonuclease activity of influenza virus polymerase.", "link"=>"http://www.mendeley.com/research/structural-analysis-specific-metal-chelating-inhibitor-binding-endonuclease-domain-influenza-ph1n1-2", "reader_count"=>73, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>4, "Librarian"=>1, "Researcher"=>21, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>23, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>9, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>4, "Librarian"=>1, "Researcher"=>21, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>23, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>9, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>10, "Agricultural and Biological Sciences"=>38, "Medicine and Dentistry"=>4, "Physics and Astronomy"=>1, "Chemistry"=>12, "Computer Science"=>1, "Immunology and Microbiology"=>2, "Earth and Planetary Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>12}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Earth and Planetary Sciences"=>{"Earth and Planetary Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>38}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"South Korea"=>1, "United States"=>3, "France"=>1, "Chile"=>1, "Germany"=>1, "India"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/597702"], "description"=>"<p><b>A:</b> Sequence alignment of the PA-Nter endonuclease from four influenza A (including the three of known atomic structure) and one influenza B strain. The secondary structure of the pH1N1 domain is shown over the alignment. Red triangles indicate conserved cation binding (His41, Glu80, Asp108, Glu119) and catalytic (Lys134) residues. Blue triangles indicate naturally variable positions amongst influenza A strains. Green triangles indicate residues interacting with the inhibitors described in this paper. <b>B:</b> Superposition of PA endonuclease structure from H3N2 (green, PDB entry 2W69), H5N1 (blue, PDB entry 3EBJ) and pH1N1 (red, this work). The two bound divalent metal ions are represented by orange spheres. Flexible region 53–73 is at the bottom right and only ordered in certain chains from the H3N2 (B chain) and pH1N1 (e.g. D chain of dTMP complex) structures. For H5N1, region 53–73 is not visible. Major secondary structure elements are shown consistent with those in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002831#ppat-1002831-g001\" target=\"_blank\">Figure 1A</a>. <b>C:</b> Divalent ion co-ordination in the native endonuclease structure. Manganese and magnesium ions are respectively pink and orange spheres and co-ordinating water molecule blue spheres and the ion co-ordination is shown with green dotted lines. For clarity, only His41 NE2 is shown (cyan sphere). <b>D:</b> Divalent ion co-ordination in the DPBA bound structure. Manganese ions are pink spheres and co-ordinating water molecule blue spheres and the ion co-ordination is shown with green dotted lines. For clarity, only His41 NE2 is shown (cyan sphere).</p>", "links"=>[], "tags"=>["pa", "endonuclease", "carries", "divalent", "cation", "binding"], "article_id"=>268190, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.g001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_PA_endonuclease_carries_a_divalent_cation_binding_site_in_its_active_center_/268190", "title"=>"The PA endonuclease carries a divalent cation binding site in its active center.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:16:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/598068"], "description"=>"<p>Each panel shows the pH1N1 domain in surface representation (green) in the same orientation with the manganese ions as pink spheres. Bound compounds are shown in surface and stick representation. Some residues underlying prominent surface features are indicated in white. <b>A</b>. Native unliganded structure. <b>B</b>. R05-3A (brick). <b>C</b>. EGCG (grey). <b>D</b>. R05-2 (yellow). In the native state, the active site cavity is large. The different compounds fill various sub-pockets of the cavity (indicated in red) and induced fit movements tend to close up the active site, but the cavity is never entirely filled.</p>", "links"=>[], "tags"=>["pockets", "pa"], "article_id"=>268563, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Active_site_pockets_of_the_PA_endonuclease_/268563", "title"=>"Active site pockets of the PA endonuclease.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:22:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/313475", "https://ndownloader.figshare.com/files/313498", "https://ndownloader.figshare.com/files/313526", "https://ndownloader.figshare.com/files/313541"], "description"=>"<div><p>It is generally recognised that novel antiviral drugs, less prone to resistance, would be a desirable alternative to current drug options in order to be able to treat potentially serious influenza infections. The viral polymerase, which performs transcription and replication of the RNA genome, is an attractive target for antiviral drugs since potent polymerase inhibitors could directly stop viral replication at an early stage. Recent structural studies on functional domains of the heterotrimeric polymerase, which comprises subunits PA, PB1 and PB2, open the way to a structure based approach to optimise inhibitors of viral replication. In particular, the unique cap-snatching mechanism of viral transcription can be inhibited by targeting either the PB2 cap-binding or PA endonuclease domains. Here we describe high resolution X-ray co-crystal structures of the 2009 pandemic H1N1 (pH1N1) PA endonuclease domain with a series of specific inhibitors, including four diketo compounds and a green tea catechin, all of which chelate the two critical manganese ions in the active site of the enzyme. Comparison of the binding mode of the different compounds and that of a mononucleotide phosphate highlights, firstly, how different substituent groups on the basic metal binding scaffold can be orientated to bind in distinct sub-pockets within the active site cavity, and secondly, the plasticity of certain structural elements of the active site cavity, which result in induced fit binding. These results will be important in optimising the design of more potent inhibitors targeting the cap-snatching endonuclease activity of influenza virus polymerase.</p> </div>", "links"=>[], "tags"=>["chelating", "inhibitor", "binding", "endonuclease", "influenza", "ph1n1", "polymerase"], "article_id"=>121831, "categories"=>["Biochemistry", "Cancer", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002831.s001", "https://dx.doi.org/10.1371/journal.ppat.1002831.s002", "https://dx.doi.org/10.1371/journal.ppat.1002831.s003", "https://dx.doi.org/10.1371/journal.ppat.1002831.s004"], "stats"=>{"downloads"=>1, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Structural_Analysis_of_Specific_Metal_Chelating_Inhibitor_Binding_to_the_Endonuclease_Domain_of_Influenza_pH1N1_2009_Polymerase/121831", "title"=>"Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-08-02 00:30:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/598198"], "description"=>"<p><b>A:</b> Superposition of diketo inhibitors and EGCG bound in the PA active site after structural alignment of the entire endonuclease domain for each structure. R05-1 in orange, R05-2 in yellow, R05-3 conformation 3A in brick, R05-3 conformation 3D in light grey and EGCG in black. Manganese ions are pink spheres. The aromatic extensions from the metal binding scaffold are inserted into different sub-pockets of the active site. <b>B:</b> Configuration of the diketo inhibitors (coloured as in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002831#ppat-1002831-g003\" target=\"_blank\">Figure 3A</a>) with respect to residue Tyr24. All panels are in the same orientation. <b>C:</b> Diagram comparing the native (cyan) and R05-3 bound form in the conformation 3A (purple). Tyr24 side-chain moves to partially stack on the chlorobenzene and Arg84 is re-ordered to stack with the benzene ring of R05-3A. Manganese ions are pink spheres and the ion co-ordination is shown with green lines. <b>D:</b> Superposition of the Cα-trace of native (cyan) and R05-3A (brick), R05-2 (yellow) and EGCG (grey) pH1N1 structures. Manganese ions are pink spheres. Much of the structure, notably the metal binding catalytic center, is relatively rigid, but there is more flexibility in the α2-a3 loop (especially at Tyr24) and also in the α5 helix (which bears the catalytic lysine).</p>", "links"=>[], "tags"=>["plasticity", "pa"], "article_id"=>268691, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.g005", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Active_site_plasticity_of_the_PA_endonuclease_/268691", "title"=>"Active site plasticity of the PA endonuclease.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:24:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/598311"], "description"=>"a<p>Fluorescence resonance energy transfer (FRET) based endonuclease activity assay. FRET measurements were determined in quadruplicates with at least two independent sets. Mean values and 95% confidence limits (as indicated) were calculated.</p>b<p>Reduction of virus induced cytopathic effect (CPE); inactive: no antiviral activity at the highest concentration tested. For CPE IC50 and CC50 values samples were applied in duplicates and IC50 values, CC50 values, and corresponding 95% confidence intervals were determined. The experiments were independently performed at least twice.</p>c<p>48 h cytotoxicity on MDCK cells.</p>d<p>No cytotoxicity at the highest concentration tested (mainly limited by solubility).</p>e<p>Apparent melting temperature Tm derived from Thermofluor measurements.</p>f<p>Not determined due to fluorescence quenching.</p>", "links"=>[], "tags"=>["inhibition", "anti-viral", "cytotoxic", "thermo-stabilisation", "ph1n1", "pa-nter", "diketo", "compounds"], "article_id"=>268796, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.t002", "stats"=>{"downloads"=>4, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Endonuclease_inhibition_FRET_anti_viral_effect_CPE_cytotoxic_dose_and_thermo_stabilisation_Tm_of_pH1N1_PA_Nter_by_diketo_compounds_and_EGCG_/268796", "title"=>"Endonuclease inhibition (FRET), anti-viral effect (CPE), cytotoxic dose and thermo-stabilisation (Tm) of pH1N1 PA-Nter by diketo compounds and EGCG.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-08-02 02:26:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/598283"], "description"=>"<p>Diagrams of each ligand are given in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002831#ppat-1002831-g002\" target=\"_blank\">Figure 2</a>.</p>", "links"=>[], "tags"=>["inhibitor", "complexes", "ligands", "crystallisation"], "article_id"=>268773, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.t001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_inhibitor_complexes_crystallised_chemical_description_of_ligands_and_crystallisation_conditions_/268773", "title"=>"Summary of inhibitor complexes crystallised, chemical description of ligands and crystallisation conditions.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-08-02 02:26:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/597820"], "description"=>"<p>Manganese ions are pink spheres and the ion co-ordination is shown with green lines. Side chains of key active site residues that interact with the compound or are close to it are shown. The orientation in each case is the same after superposition of the domain. Helix α3 (red), the α3-α3 loop and beta strands β6, β7 and β8 (yellow) are indicated in panel A. <b>A:</b> R05-3 in conformation 3A. <b>B:</b> R05-3 in conformation 3D. <b>C:</b> R05-2 (chain A). Ala20 is marked in addition (see <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002831#s3\" target=\"_blank\">discussion</a>). <b>D:</b> R05-1. <b>E:</b> EGCG. <b>F:</b> dTMP.</p>", "links"=>[], "tags"=>["diketo", "egcg", "dtmp", "ph1n1"], "article_id"=>268307, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Binding_of_diketo_inhibitors_EGCG_and_dTMP_in_the_active_site_of_pH1N1_endonuclease_/268307", "title"=>"Binding of diketo inhibitors, EGCG and dTMP in the active site of pH1N1 endonuclease.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:18:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/598337"], "description"=>"*<p>Last shell in brackets.</p>", "links"=>[], "tags"=>["refinement"], "article_id"=>268836, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.t003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Crystallographic_data_collection_and_refinement_statistics_/268836", "title"=>"Crystallographic data collection and refinement statistics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-08-02 02:27:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/597922"], "description"=>"<p><b>A:</b> Electron density for rUMP in pH1N1 PA endonuclease. Manganese ions are pink spheres, co-ordinating water molecule blue spheres and the ion co-ordination is shown with green lines. Blue contour: final 2Fo-Fc electron density at 1.0σ. Brown contour: Fo-Fc unbiased difference map at 2.8σ. Yellow contour: anomalous density at 4.0σ. <b>B:</b> Binding site of rUMP in the active site following the same scheme as in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002831#ppat-1002831-g002\" target=\"_blank\">Figure 2</a>. <b>C:</b> rUMP bound in the active site of pH1N1 PA (purple) with superposed DNA from product complex of EcoRV (brown, pdb entry 1STX). Active site residues (yellow), manganese ions (pink) and water molecules (blue) are for the rUMP structure. The position of the two DNA bases either side of the cleavage site in the EcoRV product complex is shown.</p>", "links"=>[], "tags"=>["ph1n1"], "article_id"=>268415, "categories"=>["Virology", "Biochemistry", "Chemistry", "Biophysics"], "users"=>["Eva Kowalinski", "Chloe Zubieta", "Andrea Wolkerstorfer", "Oliver H. J. Szolar", "Rob W. H. Ruigrok", "Stephen Cusack"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002831.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Binding_of_dTMP_rUMP_in_the_active_site_of_pH1N1_endonuclease_/268415", "title"=>"Binding of dTMP/rUMP in the active site of pH1N1 endonuclease.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-02 02:20:15"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"44", "full-text"=>"51", "pdf"=>"20", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"15", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2013", "month"=>"1"}
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  • {"unique-ip"=>"24", "full-text"=>"28", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2013", "month"=>"3"}
  • {"unique-ip"=>"30", "full-text"=>"33", "pdf"=>"13", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"4"}
  • {"unique-ip"=>"56", "full-text"=>"59", "pdf"=>"28", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"30", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2012", "month"=>"11"}
  • {"unique-ip"=>"32", "full-text"=>"32", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"10", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2013", "month"=>"5"}
  • {"unique-ip"=>"31", "full-text"=>"37", "pdf"=>"19", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"14", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"6"}
  • {"unique-ip"=>"28", "full-text"=>"20", "pdf"=>"15", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2013", "month"=>"7"}
  • {"unique-ip"=>"24", "full-text"=>"23", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2013", "month"=>"8"}
  • {"unique-ip"=>"29", "full-text"=>"43", "pdf"=>"8", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"9"}
  • {"unique-ip"=>"28", "full-text"=>"58", "pdf"=>"3", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"11", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"10"}
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  • {"unique-ip"=>"38", "full-text"=>"43", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2014", "month"=>"3"}
  • {"unique-ip"=>"34", "full-text"=>"32", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"5"}
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  • {"unique-ip"=>"33", "full-text"=>"32", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"4", "cited-by"=>"1", "year"=>"2014", "month"=>"8"}
  • {"unique-ip"=>"14", "full-text"=>"13", "pdf"=>"8", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"9"}
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  • {"unique-ip"=>"10", "full-text"=>"9", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"12"}
  • {"unique-ip"=>"18", "full-text"=>"14", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"1"}
  • {"unique-ip"=>"13", "full-text"=>"12", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"2"}
  • {"unique-ip"=>"10", "full-text"=>"11", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"3"}
  • {"unique-ip"=>"14", "full-text"=>"14", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"4"}
  • {"unique-ip"=>"15", "full-text"=>"18", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2015", "month"=>"5"}
  • {"unique-ip"=>"15", "full-text"=>"22", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2015", "month"=>"6"}
  • {"unique-ip"=>"16", "full-text"=>"15", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"7"}
  • {"unique-ip"=>"23", "full-text"=>"19", "pdf"=>"18", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"8"}
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Relative Metric

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