Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13.
Int J Parasitol Drugs Drug Resist
; 8(1): 145-157, 2018 04.
Article
in En
| MEDLINE
| ID: mdl-29571165
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ivermectin
/
ATP Binding Cassette Transporter, Subfamily B, Member 1
/
Structural Homology, Protein
/
Haemonchus
/
Antiparasitic Agents
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Int J Parasitol Drugs Drug Resist
Year:
2018
Document type:
Article