The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | info:eu-repo/semantics/article |
| Language: | eng |
| Published: |
MDPI AG
2022
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10171/62954 |
| _version_ | 1793400396052430848 |
|---|---|
| author | Vacas, A. (Andrés) Fernández-Rubio, C. (Celia) Algarabel, M. (Miriam) Peña-Guerrero, J. (José) Larrea, E. (Esther) Formiga, F.R. (Fabio R.) García-Sosa, A.T. (Alfonso T.) Nguewa, P.A. (Paul Alain) |
| author_facet | Vacas, A. (Andrés) Fernández-Rubio, C. (Celia) Algarabel, M. (Miriam) Peña-Guerrero, J. (José) Larrea, E. (Esther) Formiga, F.R. (Fabio R.) García-Sosa, A.T. (Alfonso T.) Nguewa, P.A. (Paul Alain) |
| author_sort | Vacas, A. (Andrés) |
| collection | DSpace |
| description | 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. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-62954 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2022 |
| publisher | MDPI AG |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-629542022-02-24T02:03:45Z The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin Vacas, A. (Andrés) Fernández-Rubio, C. (Celia) Algarabel, M. (Miriam) Peña-Guerrero, J. (José) Larrea, E. (Esther) Formiga, F.R. (Fabio R.) García-Sosa, A.T. (Alfonso T.) Nguewa, P.A. (Paul Alain) Leishmania NTD Docking Molecular dynamics Drug resistance Paromomycin Kinase Treatment LmjF.22.0810 LmJean3 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. 2022-02-23T08:28:55Z 2022-02-23T08:28:55Z 2019 info:eu-repo/semantics/article https://hdl.handle.net/10171/62954 eng info:eu-repo/semantics/openAccess application/pdf MDPI AG |
| spellingShingle | Leishmania NTD Docking Molecular dynamics Drug resistance Paromomycin Kinase Treatment LmjF.22.0810 LmJean3 Vacas, A. (Andrés) Fernández-Rubio, C. (Celia) Algarabel, M. (Miriam) Peña-Guerrero, J. (José) Larrea, E. (Esther) Formiga, F.R. (Fabio R.) García-Sosa, A.T. (Alfonso T.) Nguewa, P.A. (Paul Alain) The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin |
| title | The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin |
| title_full | The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin |
| title_fullStr | The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin |
| title_full_unstemmed | The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin |
| title_short | The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin |
| title_sort | novel serine/threonine protein kinase lmjf.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin |
| topic | Leishmania NTD Docking Molecular dynamics Drug resistance Paromomycin Kinase Treatment LmjF.22.0810 LmJean3 |
| url | https://hdl.handle.net/10171/62954 |
| work_keys_str_mv | AT vacasaandres thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT fernandezrubioccelia thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT algarabelmmiriam thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT penaguerrerojjose thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT larreaeesther thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT formigafrfabior thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT garciasosaatalfonsot thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT nguewapapaulalain thenovelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT vacasaandres novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT fernandezrubioccelia novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT algarabelmmiriam novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT penaguerrerojjose novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT larreaeesther novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT formigafrfabior novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT garciasosaatalfonsot novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin AT nguewapapaulalain novelserinethreonineproteinkinaselmjf220810fromleishmaniamajormaybeinvolvedintheresistancetodrugssuchasparomomycin |