Structural insights into recognition of chemokine receptors by Staphylococcus aureus leukotoxins

Abstract

Staphylococcus aureus (SA) leukocidin 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.

Gamma-Hemolysin Components: Computational Strategies for LukF-Hlg2 Dimer Reconstruction on a Model Membrane

“…On the contrary, the deletion, including the three subsequent residues at the N-ter of LukF, impaired the formation of pores because of the largely reduced binding activity on erythrocyte surfaces, compared to that of intact LukF. These results suggest that the N-ter region of LukF might be involved in the interaction between LukF and proteinaceous receptors on the membrane of the target cell, which was recently identified as the atypical chemokine receptor 1 ACKR1, although a structural model of the complex is still missing [ 29 , 32 ]. In this case, the formation of a non-functional LukF-Hlg2 dimer in the absence of LukF N-ter is not possible since the same LukF interface is already involved in interactions with the cell surface and the interaction with Hlg2 has to take place through the opposite face of LukF (interface I).…”

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications

“…GPCRs play a vital role in relaying information from neurotransmitters and hormone by transmitting the binding of these molecules from the extracellular side to signals on the intracellular side via binding with cellular transducers such as G protein or β-arrestin. MD simulations have been extensively used to study GPCR interactions with signaling molecules − as well as transducers in the cytosolic side. − For example, Park et al recently studied the neuropeptide Y and Y1 receptor, which is enriched in the brain and responsible for neurological processes such as food intake, anxiety, obesity, and cancer. , The cryo-EM structure shows the binding of neuropeptide Y to Y1 receptor, and MD simulations further reveal the stability and dynamics of the neuropeptide Y binding, providing a conformational ensemble of binding interactions (Figure A). Other studies have examined the GPCR-G protein binding and tried to derive a rationale for signaling through different G proteins or β-arrestin. − Zhao et al studied β2 adrenaline receptors and their differential binding interfaces with Gs, Gi, and β-arrestin 1 .…”

The chemokine receptor CCR5: multi-faceted hook for HIV-1

“…In all cases, this is an effective way to either evade immune selection or, on the opposite, to lead to a deleterious burst of the immune system (cytokine storm) [ 9 ]. This strategy is used by a wide variety of pathogens ranging from ticks [ 10 , 11 ], parasites [ 12 , 13 ] to bacteria [ 6 , 7 , 14 ] and viruses [ 15 – 30 ]. Among viruses, one can cite as examples Epstein-Barr viruses that encode a GPCR (BILF1) capable of forming a dimer with CXCR4 chemokine receptor thereby inhibiting its signaling but also human cytomegalovirus (CMV) that secretes a soluble chemokine receptor (pUL21.5) which binds selectively to the chemokine RANTES with very high affinity, blocking the interaction of RANTES with its cellular receptors (CCR5).…”