Selective binding of antimicrobial porphyrins to the heme-receptor IsdH-NEAT3 of Staphylococcus aureus.
Identifieur interne : 000421 ( Main/Exploration ); précédent : 000420; suivant : 000422Selective binding of antimicrobial porphyrins to the heme-receptor IsdH-NEAT3 of Staphylococcus aureus.
Auteurs : RBID : pubmed:23649633English descriptors
- KwdEn :
- Anti-Bacterial Agents (chemistry), Anti-Bacterial Agents (metabolism), Antigens, Bacterial (chemistry), Antigens, Bacterial (genetics), Antigens, Bacterial (metabolism), Metalloporphyrins (chemistry), Metalloporphyrins (metabolism), Metals, Heavy (chemistry), Metals, Heavy (metabolism), Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Porphyrins (chemistry), Porphyrins (metabolism), Protein Binding, Protoporphyrins (chemistry), Protoporphyrins (metabolism), Receptors, Cell Surface (chemistry), Receptors, Cell Surface (genetics), Receptors, Cell Surface (metabolism), Substrate Specificity, Thermodynamics.
- MESH :
- chemical , chemistry : Anti-Bacterial Agents, Antigens, Bacterial, Metalloporphyrins, Metals, Heavy, Porphyrins, Protoporphyrins, Receptors, Cell Surface.
- chemical , genetics : Antigens, Bacterial, Receptors, Cell Surface.
- chemical , metabolism : Anti-Bacterial Agents, Antigens, Bacterial, Metalloporphyrins, Metals, Heavy, Porphyrins, Protoporphyrins, Receptors, Cell Surface.
- Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Protein Binding, Substrate Specificity, Thermodynamics.
Abstract
The Isd (iron-regulated surface determinant) system of the human pathogen Staphylococcus aureus is responsible for the acquisition of heme from the host organism. We recently reported that the extracellular heme receptor IsdH-NEAT3 captures and transfers noniron antimicrobial porphyrins containing metals in oxidation state (III). However, it is unclear if geometric factors such as the size of the metal (ionic radius) affect binding and transfer of metalloporphyrins. We carried out an ample structural, functional, and thermodynamic analysis of the binding properties of antimicrobial indium(III)-porphyrin, which bears a much larger metal ion than the iron(III) of the natural ligand heme. The results demonstrate that the NEAT3 receptor recognizes the In(III)-containing PPIX in a manner very similar to that of heme. Site-directed mutagenesis identifies Tyr642 as the central element in the recognition mechanism as suggested from the crystal structures. Importantly, the NEAT3 receptor possesses the remarkable ability to capture dimers of metalloporphyrin. Molecular dynamics simulations reveal that IsdH-NEAT3 does not require conformational changes, or large rearrangements of the residues within its binding site, to accommodate the much larger (heme)2 ligand. We discuss the implications of these findings for the design of potent inhibitors against this family of key receptors of S. aureus.
DOI: 10.1002/pro.2276
PubMed: 23649633
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Selective binding of antimicrobial porphyrins to the heme-receptor IsdH-NEAT3 of Staphylococcus aureus.</title><author><name sortKey="Vu, Nhuan T" uniqKey="Vu N">Nhuan T Vu</name><affiliation wicri:level="1"><nlm:affiliation>Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639</wicri:regionArea></affiliation></author><author><name sortKey="Moriwaki, Yoshitaka" uniqKey="Moriwaki Y">Yoshitaka Moriwaki</name></author><author><name sortKey="Caaveiro, Jose M M" uniqKey="Caaveiro J">Jose M M Caaveiro</name></author><author><name sortKey="Terada, Tohru" uniqKey="Terada T">Tohru Terada</name></author><author><name sortKey="Tsutsumi, Hiroshi" uniqKey="Tsutsumi H">Hiroshi Tsutsumi</name></author><author><name sortKey="Hamachi, Itaru" uniqKey="Hamachi I">Itaru Hamachi</name></author><author><name sortKey="Shimizu, Kentaro" uniqKey="Shimizu K">Kentaro Shimizu</name></author><author><name sortKey="Tsumoto, Kouhei" uniqKey="Tsumoto K">Kouhei Tsumoto</name></author></titleStmt><publicationStmt><date when="2013">2013</date><idno type="doi">10.1002/pro.2276</idno><idno type="RBID">pubmed:23649633</idno><idno type="pmid">23649633</idno><idno type="wicri:Area/Main/Corpus">000631</idno><idno type="wicri:Area/Main/Curation">000631</idno><idno type="wicri:Area/Main/Exploration">000421</idno></publicationStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anti-Bacterial Agents (chemistry)</term><term>Anti-Bacterial Agents (metabolism)</term><term>Antigens, Bacterial (chemistry)</term><term>Antigens, Bacterial (genetics)</term><term>Antigens, Bacterial (metabolism)</term><term>Metalloporphyrins (chemistry)</term><term>Metalloporphyrins (metabolism)</term><term>Metals, Heavy (chemistry)</term><term>Metals, Heavy (metabolism)</term><term>Molecular Dynamics Simulation</term><term>Mutagenesis, Site-Directed</term><term>Porphyrins (chemistry)</term><term>Porphyrins (metabolism)</term><term>Protein Binding</term><term>Protoporphyrins (chemistry)</term><term>Protoporphyrins (metabolism)</term><term>Receptors, Cell Surface (chemistry)</term><term>Receptors, Cell Surface (genetics)</term><term>Receptors, Cell Surface (metabolism)</term><term>Substrate Specificity</term><term>Thermodynamics</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-Bacterial Agents</term><term>Antigens, Bacterial</term><term>Metalloporphyrins</term><term>Metals, Heavy</term><term>Porphyrins</term><term>Protoporphyrins</term><term>Receptors, Cell Surface</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antigens, Bacterial</term><term>Receptors, Cell Surface</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Anti-Bacterial Agents</term><term>Antigens, Bacterial</term><term>Metalloporphyrins</term><term>Metals, Heavy</term><term>Porphyrins</term><term>Protoporphyrins</term><term>Receptors, Cell Surface</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Molecular Dynamics Simulation</term><term>Mutagenesis, Site-Directed</term><term>Protein Binding</term><term>Substrate Specificity</term><term>Thermodynamics</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The Isd (iron-regulated surface determinant) system of the human pathogen Staphylococcus aureus is responsible for the acquisition of heme from the host organism. We recently reported that the extracellular heme receptor IsdH-NEAT3 captures and transfers noniron antimicrobial porphyrins containing metals in oxidation state (III). However, it is unclear if geometric factors such as the size of the metal (ionic radius) affect binding and transfer of metalloporphyrins. We carried out an ample structural, functional, and thermodynamic analysis of the binding properties of antimicrobial indium(III)-porphyrin, which bears a much larger metal ion than the iron(III) of the natural ligand heme. The results demonstrate that the NEAT3 receptor recognizes the In(III)-containing PPIX in a manner very similar to that of heme. Site-directed mutagenesis identifies Tyr642 as the central element in the recognition mechanism as suggested from the crystal structures. Importantly, the NEAT3 receptor possesses the remarkable ability to capture dimers of metalloporphyrin. Molecular dynamics simulations reveal that IsdH-NEAT3 does not require conformational changes, or large rearrangements of the residues within its binding site, to accommodate the much larger (heme)2 ligand. We discuss the implications of these findings for the design of potent inhibitors against this family of key receptors of S. aureus.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">23649633</PMID><DateCreated><Year>2013</Year><Month>06</Month><Day>27</Day></DateCreated><DateCompleted><Year>2014</Year><Month>01</Month><Day>16</Day></DateCompleted><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1469-896X</ISSN><JournalIssue CitedMedium="Internet"><Volume>22</Volume><Issue>7</Issue><PubDate><Year>2013</Year><Month>Jul</Month></PubDate></JournalIssue><Title>Protein science : a publication of the Protein Society</Title><ISOAbbreviation>Protein Sci.</ISOAbbreviation></Journal><ArticleTitle>Selective binding of antimicrobial porphyrins to the heme-receptor IsdH-NEAT3 of Staphylococcus aureus.</ArticleTitle><Pagination><MedlinePgn>942-53</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/pro.2276</ELocationID><Abstract><AbstractText>The Isd (iron-regulated surface determinant) system of the human pathogen Staphylococcus aureus is responsible for the acquisition of heme from the host organism. We recently reported that the extracellular heme receptor IsdH-NEAT3 captures and transfers noniron antimicrobial porphyrins containing metals in oxidation state (III). However, it is unclear if geometric factors such as the size of the metal (ionic radius) affect binding and transfer of metalloporphyrins. We carried out an ample structural, functional, and thermodynamic analysis of the binding properties of antimicrobial indium(III)-porphyrin, which bears a much larger metal ion than the iron(III) of the natural ligand heme. The results demonstrate that the NEAT3 receptor recognizes the In(III)-containing PPIX in a manner very similar to that of heme. Site-directed mutagenesis identifies Tyr642 as the central element in the recognition mechanism as suggested from the crystal structures. Importantly, the NEAT3 receptor possesses the remarkable ability to capture dimers of metalloporphyrin. Molecular dynamics simulations reveal that IsdH-NEAT3 does not require conformational changes, or large rearrangements of the residues within its binding site, to accommodate the much larger (heme)2 ligand. We discuss the implications of these findings for the design of potent inhibitors against this family of key receptors of S. aureus.</AbstractText><CopyrightInformation>Copyright Copyright © 2013 The Protein Society.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Vu</LastName><ForeName>Nhuan T</ForeName><Initials>NT</Initials><Affiliation>Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.</Affiliation></Author><Author ValidYN="Y"><LastName>Moriwaki</LastName><ForeName>Yoshitaka</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Caaveiro</LastName><ForeName>Jose M M</ForeName><Initials>JM</Initials></Author><Author ValidYN="Y"><LastName>Terada</LastName><ForeName>Tohru</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Tsutsumi</LastName><ForeName>Hiroshi</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Hamachi</LastName><ForeName>Itaru</ForeName><Initials>I</Initials></Author><Author ValidYN="Y"><LastName>Shimizu</LastName><ForeName>Kentaro</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Tsumoto</LastName><ForeName>Kouhei</ForeName><Initials>K</Initials></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>PDB</DataBankName><AccessionNumberList><AccessionNumber>3VTM</AccessionNumber></AccessionNumberList></DataBank></DataBankList><PublicationTypeList><PublicationType>Journal Article</PublicationType><PublicationType>Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2013</Year><Month>06</Month><Day>06</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Protein 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