The Novel Serine/Threonine Protein Kinase LmjF.22.0810 from <i>Leishmania major</i> may be Involved in the Resistance to Drugs such as Paromomycin
Andrés Vacas,
Celia Fernández-Rubio,
Miriam Algarabel,
José Peña-Guerrero,
Esther Larrea,
Fabio Rocha Formiga,
Alfonso T. García-Sosa,
Paul A. Nguewa
Affiliations
Andrés Vacas
Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research). Pamplona, E-31008 Navarra, Spain
Celia Fernández-Rubio
Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research). Pamplona, E-31008 Navarra, Spain
Miriam Algarabel
Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research). Pamplona, E-31008 Navarra, Spain
José Peña-Guerrero
Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research). Pamplona, E-31008 Navarra, Spain
Esther Larrea
Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research). Pamplona, E-31008 Navarra, Spain
Fabio Rocha Formiga
Aggeu Magalhães Institute, Oswaldo Cruz Foundation (FIOCRUZ). Graduate Program in Applied Cellular and Molecular Biology (BCMA), University of Pernambuco (UPE), Recife/PE 50.670-420, Brazil
Alfonso T. García-Sosa
Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 54011, Estonia
Paul A. Nguewa
Department of Microbiology and Parasitology, ISTUN Institute of Tropical Health, University of Navarra, IdiSNA (Navarra Institute for Health Research). Pamplona, E-31008 Navarra, Spain
The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.
