Structural model， functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13.

Haemonchus contortus， one of the most economically important parasites of small ruminants， has become resistant to the anthelmintic ivermectin. Deciphering the role of P-glycoproteins in ivermectin resistance is desirable for understanding and overcoming this resistance. In the model nematode， Caenorhabditis elegans， P-glycoprotein-13 is expressed in the amphids， important neuronal structures for ivermectin activity. We have focused on its ortholog in the parasite， Hco-Pgp-13. A 3D model of Hco-Pgp-13， presenting an open inward-facing conformation， has been constructed by homology with the Cel-Pgp-1 crystal structure. In silico docking calculations predicted high affinity binding of ivermectin and actinomycin D to the inner chamber of the protein. Following in vitro expression， we showed that ivermectin and actinomycin D modulated Hco-Pgp-13 ATPase activity with high affinity. Finally， we found in vivo Hco-Pgp-13 localization in epithelial， pharyngeal and neuronal tissues. Taken together， these data suggest a role for Hco-Pgp-13 in ivermectin transport， which could contribute to anthelmintic resistance.