Antihistamine response: a dynamically refined function at the host-tick interface

Particle and Fibre Toxicology

James J Valdés¹ 

[1] Institute of Parasitology, Biology Centre of the Academy of Sciences of the Czech Republic, ?eské Bud?jovice, 37005, Czech Republic

关键词: Ticks;    Tick saliva;    Competitive binding;    Lipocalin;    Histamine;    Dynamics;   

Others  :  1149494
DOI  :  10.1186/s13071-014-0491-9

 received in 2014-08-13, accepted in 2014-10-16,  发布年份 2014

【 摘 要 】

Background

Ticks counteract host inflammatory responses by secreting proteins from their saliva that compete for histamine binding. Among these tick salivary proteins are lipocalins, antiparallel beta-barrel proteins that sequester small molecules. A tick salivary lipocalin has been structurally resolved and experimentally shown to efficiently compete for histamine with its native receptor (e.g., H1 histamine receptor). To date, molecular dynamics simulations focus on protein-protein and protein-ligand interactions, but there are currently no studies for simultaneous ligand exploration between two competing proteins.

Methods

Aided by state-of-the-art, high-throughput computational methods, the current study simulated and analyzed the dynamics of competitive histamine binding at the tick-host interface using the available crystal structures of both the tick salivary lipocalin histamine-binding protein from Rhipicephalus appendiculatus and the human histamine receptor 1.

Results

The attraction towards the tick salivary lipocalin seems to depend on the protonated (adding a hydrogen ion) state of histamine since the current study shows that as histamine becomes more protonated it increases its exploration for the tick salivary lipocalin. This implies that during tick feeding, histamine may need to be protonated for the tick salivary lipocalin to efficiently sequester it in order to counteract inflammation. Additionally, the beta-hairpin loops (at both ends of the tick salivary lipocalin barrel) were reported to have a functional role in sequestering histamine and the results in the current study concur and provide evidence for this hypothesis. These beta-hairpin loops of the tick salivary lipocalin possess more acidic residues than a structurally similar but functionally unrelated lipocalin from the butterfly, Pieris brassicae; comparative results indicate these acidic residues may be responsible for the ability of the tick lipocalin to out-compete the native (H1) receptor for histamine.

Conclusions

Three explanatory types of data can be obtained from the current study: (i) the dynamics of multiple binding sites, (ii) competition between two proteins for a ligand, and (iii) the intrinsic molecular components involved in the competition. These data can provide further insight at the atomic level of the host-tick interface that cannot be experimentally determined. Additionally, the methods used in this study can be applied in rationally designing drugs.

【 授权许可】

   
2014 Valdes; licensee BioMed Central Ltd.

【 图 表 】

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