Cargando…
c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation
The cancer drug Ruxolitinib is a potent janus kinase inhibitor approved for the treatment of the myeloproliferative neoplasms. In addition, Ruxolitinib has weak inhibitory activity against a panel of other kinases, including Src kinase. There is no structural information of Ruxolitinib binding to an...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157781/ https://www.ncbi.nlm.nih.gov/pubmed/25197973 http://dx.doi.org/10.1371/journal.pone.0106225 |
_version_ | 1782333929394536448 |
---|---|
author | Duan, Yankun Chen, Lin Chen, Yongheng Fan, Xue-gong |
author_facet | Duan, Yankun Chen, Lin Chen, Yongheng Fan, Xue-gong |
author_sort | Duan, Yankun |
collection | PubMed |
description | The cancer drug Ruxolitinib is a potent janus kinase inhibitor approved for the treatment of the myeloproliferative neoplasms. In addition, Ruxolitinib has weak inhibitory activity against a panel of other kinases, including Src kinase. There is no structural information of Ruxolitinib binding to any kinase. In this paper, we determined the crystal structure of c-Src kinase domain in complex of Ruxolitinib at a resolution of 2.26 Å. C-Src kinase domain adopts the DFG-in active conformation upon Ruxolitinib binding, indicating Ruxolitinib is a type I inhibitor for c-Src. Ruxolitinib forms two hydrogen bonds with Met341, a water-mediated hydrogen bond with Thr338, and a number of van der Waals contacts with c-Src. Ruxolitinib was then docked into the ligand-binding pocket of a previously solved JAK1 structure. From the docking result, Ruxolitinib also binds JAK1 as a type I inhibitor, with more interactions and a higher shape complementarity with the ligand-binding pocket of JAK1 compared to that of c-Src. Since Ruxolitinib is a relatively small inhibitor and there is sizeable cavity between Ruxolitinib and c-Src ligand-binding pocket, we propose to modify Ruxolitinib to develop more potent inhibitors to c-Src. |
format | Online Article Text |
id | pubmed-4157781 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41577812014-09-09 c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation Duan, Yankun Chen, Lin Chen, Yongheng Fan, Xue-gong PLoS One Research Article The cancer drug Ruxolitinib is a potent janus kinase inhibitor approved for the treatment of the myeloproliferative neoplasms. In addition, Ruxolitinib has weak inhibitory activity against a panel of other kinases, including Src kinase. There is no structural information of Ruxolitinib binding to any kinase. In this paper, we determined the crystal structure of c-Src kinase domain in complex of Ruxolitinib at a resolution of 2.26 Å. C-Src kinase domain adopts the DFG-in active conformation upon Ruxolitinib binding, indicating Ruxolitinib is a type I inhibitor for c-Src. Ruxolitinib forms two hydrogen bonds with Met341, a water-mediated hydrogen bond with Thr338, and a number of van der Waals contacts with c-Src. Ruxolitinib was then docked into the ligand-binding pocket of a previously solved JAK1 structure. From the docking result, Ruxolitinib also binds JAK1 as a type I inhibitor, with more interactions and a higher shape complementarity with the ligand-binding pocket of JAK1 compared to that of c-Src. Since Ruxolitinib is a relatively small inhibitor and there is sizeable cavity between Ruxolitinib and c-Src ligand-binding pocket, we propose to modify Ruxolitinib to develop more potent inhibitors to c-Src. Public Library of Science 2014-09-08 /pmc/articles/PMC4157781/ /pubmed/25197973 http://dx.doi.org/10.1371/journal.pone.0106225 Text en © 2014 Duan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Duan, Yankun Chen, Lin Chen, Yongheng Fan, Xue-gong c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation |
title | c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation |
title_full | c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation |
title_fullStr | c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation |
title_full_unstemmed | c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation |
title_short | c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation |
title_sort | c-src binds to the cancer drug ruxolitinib with an active conformation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157781/ https://www.ncbi.nlm.nih.gov/pubmed/25197973 http://dx.doi.org/10.1371/journal.pone.0106225 |
work_keys_str_mv | AT duanyankun csrcbindstothecancerdrugruxolitinibwithanactiveconformation AT chenlin csrcbindstothecancerdrugruxolitinibwithanactiveconformation AT chenyongheng csrcbindstothecancerdrugruxolitinibwithanactiveconformation AT fanxuegong csrcbindstothecancerdrugruxolitinibwithanactiveconformation |