Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins
Staphylococcus aureus (SA) leukocidin ED (LukED) belongs to a family of bicomponent pore forming toxins that play important roles in SA immune evasion and nutrient acquisition. LukED targets specific G protein-coupled chemokine receptors to lyse human erythrocytes (red blood cells) and leukocytes (w...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/72555 |
| _version_ | 1811203083470897152 |
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| author | Paul Lambey Omolade Otun Xiaojing Cong François Hoh Luc Brunel Pascal Verdié Claire M Grison Fanny Peysson Sylvain Jeannot Thierry Durroux Cherine Bechara Sébastien Granier Cédric Leyrat |
| author_facet | Paul Lambey Omolade Otun Xiaojing Cong François Hoh Luc Brunel Pascal Verdié Claire M Grison Fanny Peysson Sylvain Jeannot Thierry Durroux Cherine Bechara Sébastien Granier Cédric Leyrat |
| author_sort | Paul Lambey |
| collection | DOAJ |
| description | Staphylococcus aureus (SA) leukocidin ED (LukED) belongs to a family of bicomponent pore forming toxins that play important roles in SA immune evasion and nutrient acquisition. LukED targets specific G protein-coupled chemokine receptors to lyse human erythrocytes (red blood cells) and leukocytes (white blood cells). The first recognition step of receptors is critical for specific cell targeting and lysis. The structural and molecular bases for this mechanism are not well understood but could constitute essential information to guide antibiotic development. Here, we characterized the interaction of LukE with chemokine receptors ACKR1, CCR2, and CCR5 using a combination of structural, pharmacological, and computational approaches. First, crystal structures of LukE in complex with a small molecule mimicking sulfotyrosine side chain (p-cresyl sulfate) and with peptides containing sulfotyrosines issued from receptor sequences revealed the location of receptor sulfotyrosine binding sites in the toxins. Then, by combining previous and novel experimental data with protein docking, classical and accelerated weight histogram (AWH) molecular dynamics we propose models of the ACKR1-LukE and CCR5-LukE complexes. This work provides novel insights into chemokine receptor recognition by leukotoxins and suggests that the conserved sulfotyrosine binding pocket could be a target of choice for future drug development. |
| first_indexed | 2024-04-12T02:49:36Z |
| format | Article |
| id | doaj.art-6a2d413ff8244168837148838406e319 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:49:36Z |
| publishDate | 2022-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6a2d413ff8244168837148838406e3192022-12-22T03:51:03ZengeLife Sciences Publications LtdeLife2050-084X2022-03-011110.7554/eLife.72555Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxinsPaul Lambey0Omolade Otun1Xiaojing Cong2François Hoh3Luc Brunel4Pascal Verdié5https://orcid.org/0000-0002-5807-0293Claire M Grison6Fanny Peysson7Sylvain Jeannot8Thierry Durroux9Cherine Bechara10Sébastien Granier11https://orcid.org/0000-0003-1550-3658Cédric Leyrat12https://orcid.org/0000-0003-0189-0562Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceCentre de Biochimie Structurale, CNRS UMR 5048-INSERM 1054- University of Montpellier, Montpellier, FranceInstitut des Biomolécules Max Mousseron (IBMM), University of Montpellier, Montpellier, FranceInstitut des Biomolécules Max Mousseron (IBMM), University of Montpellier, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France; Institut Universitaire de France, Paris, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, FranceStaphylococcus aureus (SA) leukocidin ED (LukED) belongs to a family of bicomponent pore forming toxins that play important roles in SA immune evasion and nutrient acquisition. LukED targets specific G protein-coupled chemokine receptors to lyse human erythrocytes (red blood cells) and leukocytes (white blood cells). The first recognition step of receptors is critical for specific cell targeting and lysis. The structural and molecular bases for this mechanism are not well understood but could constitute essential information to guide antibiotic development. Here, we characterized the interaction of LukE with chemokine receptors ACKR1, CCR2, and CCR5 using a combination of structural, pharmacological, and computational approaches. First, crystal structures of LukE in complex with a small molecule mimicking sulfotyrosine side chain (p-cresyl sulfate) and with peptides containing sulfotyrosines issued from receptor sequences revealed the location of receptor sulfotyrosine binding sites in the toxins. Then, by combining previous and novel experimental data with protein docking, classical and accelerated weight histogram (AWH) molecular dynamics we propose models of the ACKR1-LukE and CCR5-LukE complexes. This work provides novel insights into chemokine receptor recognition by leukotoxins and suggests that the conserved sulfotyrosine binding pocket could be a target of choice for future drug development.https://elifesciences.org/articles/72555S. aureusmolecular dynamicsGPCRscrystallographychemokine receptorssulfotyrosine |
| spellingShingle | Paul Lambey Omolade Otun Xiaojing Cong François Hoh Luc Brunel Pascal Verdié Claire M Grison Fanny Peysson Sylvain Jeannot Thierry Durroux Cherine Bechara Sébastien Granier Cédric Leyrat Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins eLife S. aureus molecular dynamics GPCRs crystallography chemokine receptors sulfotyrosine |
| title | Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins |
| title_full | Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins |
| title_fullStr | Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins |
| title_full_unstemmed | Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins |
| title_short | Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins |
| title_sort | structural insights into recognition of chemokine receptors by staphylococcus aureus leukotoxins |
| topic | S. aureus molecular dynamics GPCRs crystallography chemokine receptors sulfotyrosine |
| url | https://elifesciences.org/articles/72555 |
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