Biomaterial Database

Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins. 2022

Paul Lambey, and Omolade Otun, and Xiaojing Cong, and François Hoh, and Luc Brunel, and Pascal Verdié, and Claire M Grison, and Fanny Peysson, and Sylvain Jeannot, and Thierry Durroux, and Cherine Bechara, and Sébastien Granier, and Cédric Leyrat

Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.

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.

UI	MeSH Term	Description	Entries
D007956	Leukocidins	Pore forming proteins originally discovered for toxic activity to LEUKOCYTES. They are EXOTOXINS produced by some pathogenic STAPHYLOCOCCUS and STREPTOCOCCUS that destroy leukocytes by lysis of the cytoplasmic granules and are partially responsible for the pathogenicity of the organisms.	Leucocidin,Leukocidin,Leukocidin Proteins,Proteins, Leukocidin
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013203	Staphylococcal Infections	Infections with bacteria of the genus STAPHYLOCOCCUS.	Infections, Staphylococcal,Staphylococcus aureus Infection,Staphylococcal Infection,Staphylococcus aureus Infections
D013211	Staphylococcus aureus	Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications.
D043562	Receptors, G-Protein-Coupled	The largest family of cell surface receptors involved in SIGNAL TRANSDUCTION. They share a common structure and signal through HETEROTRIMERIC G-PROTEINS.	G Protein Coupled Receptor,G-Protein-Coupled Receptor,G-Protein-Coupled Receptors,G Protein Coupled Receptors,Receptor, G-Protein-Coupled,Receptors, G Protein Coupled
D057131	Immune Evasion	Methods used by pathogenic organisms to evade a host's immune system.	Evasion, Immune,Evasions, Immune,Immune Evasions
D019707	Receptors, Chemokine	Cell surface glycoproteins that bind to chemokines and thus mediate the migration of pro-inflammatory molecules. The receptors are members of the seven-transmembrane G protein-coupled receptor family. Like the CHEMOKINES themselves, the receptors can be divided into at least three structural branches: CR, CCR, and CXCR, according to variations in a shared cysteine motif.	Chemokine Receptor,Chemokine Receptors,Receptor, Chemokine