Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from Yersinia pestis
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{"title"=>"Biochemical, structural and molecular dynamics analyses of the potential virulence factor RipA from Yersinia pestis", "type"=>"journal", "authors"=>[{"first_name"=>"Rodrigo", "last_name"=>"Torres", "scopus_author_id"=>"55865568396"}, {"first_name"=>"Robert V.", "last_name"=>"Swift", "scopus_author_id"=>"23989825500"}, {"first_name"=>"Nicholas", "last_name"=>"Chim", "scopus_author_id"=>"14057746300"}, {"first_name"=>"Nicole", "last_name"=>"Wheatley", "scopus_author_id"=>"54993121800"}, {"first_name"=>"Benson", "last_name"=>"Lan", "scopus_author_id"=>"53866569300"}, {"first_name"=>"Brian R.", "last_name"=>"Atwood", "scopus_author_id"=>"53866103700"}, {"first_name"=>"Céline", "last_name"=>"Pujol", "scopus_author_id"=>"7006222143"}, {"first_name"=>"Banu", "last_name"=>"Sankaran", "scopus_author_id"=>"36454281000"}, {"first_name"=>"James B.", "last_name"=>"Bliska", "scopus_author_id"=>"7004681489"}, {"first_name"=>"Rommie E.", "last_name"=>"Amaro", "scopus_author_id"=>"8730822500"}, {"first_name"=>"Celia W.", "last_name"=>"Goulding", "scopus_author_id"=>"7003330133"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"21966419", "doi"=>"10.1371/journal.pone.0025084", "sgr"=>"80053157138", "arxiv"=>"PMC3180442", "isbn"=>"1932-6203 (Electronic) 1932-6203 (Linking)", "scopus"=>"2-s2.0-80053157138", "issn"=>"19326203", "pui"=>"362627646"}, "id"=>"e12e297a-5e2c-38a6-ac27-118c6b77bb94", "abstract"=>"Human diseases are attributed in part to the ability of pathogens to evade the eukaryotic immune systems. A subset of these pathogens has developed mechanisms to survive in human macrophages. Yersinia pestis, the causative agent of the bubonic plague, is a predominately extracellular pathogen with the ability to survive and replicate intracellularly. A previous study has shown that a novel rip (required for intracellular proliferation) operon (ripA, ripB and ripC) is essential for replication and survival of Y. pestis in postactivated macrophages, by playing a role in lowering macrophage-produced nitric oxide (NO) levels. A bioinformatics analysis indicates that the rip operon is conserved among a distally related subset of macrophage-residing pathogens, including Burkholderia and Salmonella species, and suggests that this previously uncharacterized pathway is also required for intracellular survival of these pathogens. The focus of this study is ripA, which encodes for a protein highly homologous to 4-hydroxybutyrate-CoA transferase; however, biochemical analysis suggests that RipA functions as a butyryl-CoA transferase. The 1.9 Å X-ray crystal structure reveals that RipA belongs to the class of Family I CoA transferases and exhibits a unique tetrameric state. Molecular dynamics simulations are consistent with RipA tetramer formation and suggest a possible gating mechanism for CoA binding mediated by Val227. Together, our structural characterization and molecular dynamic simulations offer insights into acyl-CoA specificity within the active site binding pocket, and support biochemical results that RipA is a butyryl-CoA transferase. We hypothesize that the end product of the rip operon is butyrate, a known anti-inflammatory, which has been shown to lower NO levels in macrophages. Thus, the results of this molecular study of Y. pestis RipA provide a structural platform for rational inhibitor design, which may lead to a greater understanding of the role of RipA in this unique virulence pathway.", "link"=>"http://www.mendeley.com/research/biochemical-structural-molecular-dynamics-analyses-potential-virulence-factor-ripa-yersinia-pestis", "reader_count"=>21, "reader_count_by_academic_status"=>{"Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>6, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>6, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>11, "Chemistry"=>5, "Social Sciences"=>1, "Computer Science"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>5}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "reader_count_by_country"=>{"United States"=>2}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/731126"], "description"=>"<p>Representative DSF melting curves of 5 mM RipA incubated in the absence or presence of 20 mM CoA or CoA-derivatives at pH 7.4. Increased RipA thermostability is indicated by a rightward curve shift as seen for acetyl-CoA and succinyl-CoA. All experiments were at least performed in duplicate.</p>", "links"=>[], "tags"=>["ripa", "binding", "coa"], "article_id"=>401467, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_RipA_and_its_binding_to_CoA_and_CoA_derivatives_/401467", "title"=>"Analysis of RipA and its binding to CoA and CoA-derivatives.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:24:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/731323"], "description"=>"<p>(<b>A</b>) Overall structure of <i>Y. pestis</i> RipA, the N-terminal and C-terminal domains are colored blue and red, respectively, connected via an ordered loop colored in green. The proposed active site glutamate, Glu249, and Val227, the key residue proposed to be involved in an active site “gating mechanism” are in stick representation with carbon, oxygen and nitrogen atoms are colored, yellow, red and blue, respectively. (<b>B</b>) Depiction of the tight dimer of RipA where each monomer of the dimer is colored in cyan and orange. The black circles indicate active site Glu249 and the three-residue loop (G-V227-G), which are in stick representation where oxygen and red atoms are colored red and blue, respectively, and Glu249 carbon atoms are colored yellow. (<b>C</b>) Superposition of the two monomers from the dimer, where the only difference between both subunits is in the three-residue loop (G-V227-G). (<b>D</b>) Electron density (shown in blue mesh) surrounding the GVG of the three-residue loop from each monomer of the dimer.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "physiology", "cell biology", "neuroscience", "Biochemistry", "Infectious diseases", "Computational biology"], "article_id"=>401673, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structure_of_RipA_/401673", "title"=>"Structure of RipA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:27:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/731730"], "description"=>"<p>(<b>A</b>) Val227 affects acyl-CoA binding pocket volume. In the overview (left), and the close-up (right) the representative small-volume conformation is shown in cyan, while the representative large-volume conformation is shown in orange. In the overview, molecular surfaces of residues within 10 Å are shown, while the remainder of the residues are rendered in cartoon. In the large-volume state, Val227 is stabilized by interactions with a pocket formed by the side chains of Val250, Met197, Met282 and Asn252; in the overview, these residues are rendered as colored surfaces and labeled (the methionines are colored yellow, asparagine is colored red and the valine is colored blue); in the close-up, these residues are rendered in van der Waals spheres and colored according to atom type. Glu249 is shown in orange spheres for reference. (<b>B</b>) Putative acyl binding pocket. Phe85 rotates during MD, increasing the available volume in a largely hydrophobic pocket adjacent to the putative catalytic Glu249. The position of Phe85 in the crystal structure is shown in cyan; a representative conformation from MD is shown in orange. Other residues lining the pocket that do not undergo substantial rearrangements during dynamics, along with Glu249, are shown in white. Pocket expansion likely facilitates acyl binding during the acyl transfer reaction.</p>", "links"=>[], "tags"=>["perturbations", "acyl-coa", "binding"], "article_id"=>402074, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g006", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MD_perturbations_in_the_acyl_CoA_binding_pocket_/402074", "title"=>"MD perturbations in the acyl-CoA binding pocket.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:34:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/731457"], "description"=>"<p>(<b>A</b>) Tetrameric state of RipA formed by the crystallographic symmetry axis at the dimer-dimer interface. Each monomer of the dimer are colored in cyan and orange, and the crystallographic symmetry axis is marked with a red line, and is at the dimer-dimer interface of the tetramer. Entrance to each active site of the four monomers is indicated with an arrow. (<b>B</b>) Hydrogen-bonding network at the dimer-dimer interface, one cyan and one orange monomer. Key interacting residues are in stick representation, where oxygen and nitrogen atoms are colored in red and blue, respectively. Black dashed lines indicate hydrogen bonds (less than 4 Å). (<b>C</b>) Size exclusion chromatogram of RipA. Bold line is RipA and dashed line is a protein standard. (<b>D</b>) Top view of SAXS data with the overlay of RipA tetramer with the electron-density envelope using CHIMERA. The envelope is calculated from an average of 10 GASBOR runs with P2 symmetry and 1756 residues.</p>", "links"=>[], "tags"=>["immunology", "microbiology", "physiology", "cell biology", "neuroscience", "Biochemistry", "Infectious diseases", "Computational biology"], "article_id"=>401789, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g004", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RipA_is_a_tetramer_/401789", "title"=>"RipA is a tetramer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:29:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/731226"], "description"=>"<p>(<b>A</b>) CoA transferase activity of RipA was measured with a variety of CoA-derivatives. Each 100 µL reaction mixture contained 50 µM CoA-derivative, 100 mM sodium acetate, 100 mM Tris pH 7.0, 1 mM oxaloacetate, 0.5 U citrate synthase and 1 mM DTNB. The reaction was initiated with the addition of 10 µM RipA and was incubated at room temperature for 30 min monitoring the release of free coenzyme A at 412 nm, which detects the formation of the nitrothiobenzoate dianion. CoA specificity was tested using different CoA donors with negative controls for background activity (without RipA) and CoA hydrolase (alternative CoA reaction). (<b>B</b>) Substrate specificity of RipA for the carboxylic acid. Acetate competed with a second acid in equimolar (10 mM each) in the presence of butyryl-CoA (100 mM). The remaining reaction mixture is the same as (<b>A</b>). The relative activities are compared to the reaction with no second carboxylic acid (labeled ‘none’).</p>", "links"=>[], "tags"=>["transferase"], "article_id"=>401574, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CoA_transferase_activity_of_RipA_/401574", "title"=>"CoA transferase activity of RipA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:26:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/731876"], "description"=>"<p>Positive and negative electric isopotential surfaces, with values +70 kT/e and −70 kT/e, respectively, are shown in blue and red wire frame mesh. The N-terminal domain is colored blue, the C-terminal domain red, and linker green. For reference, Glu249 is shown in yellow van der Waals representation and labeled, and RipA is oriented as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025084#pone-0025084-g003\" target=\"_blank\">Figure 3A</a>.</p>", "links"=>[], "tags"=>["averaged"], "article_id"=>402223, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g008", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ensemble_averaged_electrostatics_/402223", "title"=>"Ensemble averaged electrostatics.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:37:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/731985"], "description"=>"<p>Each melting curve is fit by a nonlinear regression analysis using the Boltzmann function (GraphPad Prism) and the <i>T<sub>m</sub></i> value is determined by the inflection point of the transition curve as defined from 35–65°C.</p>", "links"=>[], "tags"=>["ripa", "coa"], "article_id"=>402333, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.t002", "stats"=>{"downloads"=>3, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DSF_derived_T_m_values_for_RipA_in_the_absence_or_presence_of_CoA_and_CoA_derivatives_/402333", "title"=>"DSF-derived <i>T<sub>m</sub></i> values for RipA in the absence or presence of CoA and CoA-derivatives.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-09-26 00:38:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/732031"], "description"=>"<p>Bioinformatics analysis of Rip proteins performed on bacterial genomes available in the NCBI database. The table represents select pathogens harboring Rip homologs with a minimum of 45% amino acid identity and putatively organized in an operon (maximum intergenic distance of 1 kb). Percent identity between the <i>Y. pestis</i> Rip protein and the bacterial homolog is shown.</p>", "links"=>[], "tags"=>["operon", "conserved", "distantly-related"], "article_id"=>402379, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_rip_operon_is_conserved_across_distantly_related_pathogens_/402379", "title"=>"The <i>rip</i> operon is conserved across distantly-related pathogens.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-09-26 00:39:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/731565"], "description"=>"<p>Amino acid numbering and secondary structure elements above the sequence correspond to that of <i>Y. pestis</i> RipA, whereby tubes and arrows represent a-helices and b-strands, respectively. The conserved active site residue, Glu249, and the proposed key residue in the substrate gating-mechanism, Val227, are boxed. Residues donated with an open circle form the dimer-dimer interface, and those donated with a filled circle represent residues within the binding pocket of the acyl moiety for acyl-CoA. The sequence alignment of Family I CoA transferase homologs was made with ClustalW <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025084#pone.0025084-Larkin1\" target=\"_blank\">[55]</a>. The black line represents the insert in <i>Escherichia coli</i> YdiF. Abbreviations of the species names for Family I CoA transferases are as follows: YP-RipA, <i>Yersinia pestis</i> RipA; BP-RipA, <i>Burkholderia mallei</i> RipA; ST-RipA, <i>Salmonella typhimurium</i> RipA; SO-4HB, <i>Shewanella oneidensis</i> 4-HB-CoAT; PG-4HB, <i>Porphyromonas gingivalis</i> 4-HB-CoAT; CA-4HB, <i>Clostridium aminobutyricum</i> 4-HB-CoAT; EC-YdiF, <i>Escherichia coli</i> YdiF; SS-SCOT, <i>Sus scrofa</i> SCOT; RS-But, <i>Roseburia</i> sp. Butyryl-CoA transferase.</p>", "links"=>[], "tags"=>["members", "coa"], "article_id"=>401913, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g005", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sequence_comparison_of_members_of_the_Family_I_CoA_transferases_/401913", "title"=>"Sequence comparison of members of the Family I CoA transferases.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:31:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/732085"], "description"=>"¶<p>Statistics for the highest resolution shell are given in (brackets).</p>a<p>R<sub>merge</sub> = ∑|I−<i>|/∑I.</i></p><i>b<p>R<i><sub>work</sub></i> = ∑|F<sub>obs</sub>−F<sub>calc</sub>|/∑F<sub>obs</sub> R<i><sub>free</sub></i> was computed identically except where all reflections belong to a test set of 5% randomly selected data.</p></i>", "links"=>[], "tags"=>["diffraction", "atomic", "refinement", "ripa", "crystallized"], "article_id"=>402423, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.t004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_X_ray_diffraction_data_collection_and_atomic_refinement_for_Y_pestis_RipA_crystallized_in_the_presence_of_various_CoA_derivatives_/402423", "title"=>"X-ray diffraction data collection and atomic refinement for <i>Y. pestis</i> RipA crystallized in the presence of various CoA-derivatives.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-09-26 00:40:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/731954"], "description"=>"<p>CoA transferase activity of RipA was measured with a variety of CoA-derivatives at varying concentrations. Each 100 µL reaction mixture contained CoA-derivative, 50 mM sodium acetate, 100 mM Tris pH 7.0, 1 mM oxaloacetate, 0.5 U citrate synthase and 1 mM DTNB. The reaction was initiated with the addition of 5 µM RipA and was incubated at room temperature for 30 min monitoring the release of free coenzyme A at 412 nm, which detects the formation of the nitrothiobenzoate dianion.</p>", "links"=>[], "tags"=>["constants", "coa-derivative", "substrates"], "article_id"=>402294, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.t003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Kinetic_constants_for_CoA_derivative_substrates_of_RipA_/402294", "title"=>"Kinetic constants for CoA-derivative substrates of RipA.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-09-26 00:38:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/731803"], "description"=>"<p>(<b>A</b>) Butyryl-CoA was modeled into chain A of the crystal structure. Phe85 closes the predicted acyl-binding pocket, forcing the butyryl to bend back toward the AMP-CoA moiety. The distance between the Glu249 putative nucleophile and the carbon atom of the carbonyl elecrophile is 4.95 Å. (<b>B</b>) Butyryl-CoA was modeled into a conformation sampled from the MD simulation. Phe85 rotates, opening the predicted acyl-binding pocket and allowing the butyryl to adopt a more extended conformation. In the more extended conformation, the distance between Glu249 and the carbonyl electrophile closes to 3.74 Å. In both (A) and (B) protein residues are colored by atom type with green carbon atoms, while butyryl-CoA is colored by atom type with cyan carbon atoms; residues not shown explicitly are rendered in white cartoon.</p>", "links"=>[], "tags"=>["butyryl-coa", "ripa"], "article_id"=>402148, "categories"=>["Microbiology", "Biochemistry", "Infectious Diseases", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025084.g007", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Modeling_butyryl_CoA_into_the_RipA_structure_/402148", "title"=>"Modeling butyryl-CoA into the RipA structure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-26 00:35:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/369526", "https://ndownloader.figshare.com/files/369575", "https://ndownloader.figshare.com/files/369606", "https://ndownloader.figshare.com/files/369650", "https://ndownloader.figshare.com/files/369675", "https://ndownloader.figshare.com/files/369703", "https://ndownloader.figshare.com/files/369722", "https://ndownloader.figshare.com/files/369746", "https://ndownloader.figshare.com/files/369771", "https://ndownloader.figshare.com/files/369803", "https://ndownloader.figshare.com/files/369856"], "description"=>"<div><p>Human diseases are attributed in part to the ability of pathogens to evade the eukaryotic immune systems. A subset of these pathogens has developed mechanisms to survive in human macrophages. <em>Yersinia pestis</em>, the causative agent of the bubonic plague, is a predominately extracellular pathogen with the ability to survive and replicate intracellularly. A previous study has shown that a novel <em>rip</em> (required for intracellular proliferation) operon (<em>ripA</em>, <em>ripB</em> and <em>ripC</em>) is essential for replication and survival of <em>Y. pestis</em> in postactivated macrophages, by playing a role in lowering macrophage-produced nitric oxide (NO) levels. A bioinformatics analysis indicates that the <em>rip</em> operon is conserved among a distally related subset of macrophage-residing pathogens, including <em>Burkholderia</em> and <em>Salmonella</em> species, and suggests that this previously uncharacterized pathway is also required for intracellular survival of these pathogens. The focus of this study is <em>ripA</em>, which encodes for a protein highly homologous to 4-hydroxybutyrate-CoA transferase; however, biochemical analysis suggests that RipA functions as a butyryl-CoA transferase. The 1.9 Å X-ray crystal structure reveals that RipA belongs to the class of Family I CoA transferases and exhibits a unique tetrameric state. Molecular dynamics simulations are consistent with RipA tetramer formation and suggest a possible gating mechanism for CoA binding mediated by Val227. Together, our structural characterization and molecular dynamic simulations offer insights into acyl-CoA specificity within the active site binding pocket, and support biochemical results that RipA is a butyryl-CoA transferase. We hypothesize that the end product of the <em>rip</em> operon is butyrate, a known anti-inflammatory, which has been shown to lower NO levels in macrophages. Thus, the results of this molecular study of <em>Y. pestis</em> RipA provide a structural platform for rational inhibitor design, which may lead to a greater understanding of the role of RipA in this unique virulence pathway.</p> </div>", "links"=>[], "tags"=>["molecular", "analyses", "virulence", "ripa"], "article_id"=>133010, "categories"=>["Cancer", "Microbiology", "Biochemistry", "Immunology", "Physiology", "Biological Sciences", "Neuroscience", "Cell Biology"], "users"=>["Rodrigo Torres", "Robert V. Swift", "Nicholas Chim", "Nicole Wheatley", "Benson Lan", "Brian R. Atwood", "Céline Pujol", "Banu Sankaran", "James B. Bliska", "Rommie E. Amaro", "Celia W. Goulding"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025084.s001", "https://dx.doi.org/10.1371/journal.pone.0025084.s002", "https://dx.doi.org/10.1371/journal.pone.0025084.s003", "https://dx.doi.org/10.1371/journal.pone.0025084.s004", "https://dx.doi.org/10.1371/journal.pone.0025084.s005", "https://dx.doi.org/10.1371/journal.pone.0025084.s006", "https://dx.doi.org/10.1371/journal.pone.0025084.s007", "https://dx.doi.org/10.1371/journal.pone.0025084.s008", "https://dx.doi.org/10.1371/journal.pone.0025084.s009", "https://dx.doi.org/10.1371/journal.pone.0025084.s010", "https://dx.doi.org/10.1371/journal.pone.0025084.s011"], "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Biochemical_Structural_and_Molecular_Dynamics_Analyses_of_the_Potential_Virulence_Factor_RipA_from_Yersinia_pestis_/133010", "title"=>"Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from <em>Yersinia pestis</em>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-09-26 00:50:10"}

PMC Usage Stats | Further Information

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Relative Metric

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