Download Mendeleyc-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation
Duan, Y., Chen, L., Chen, Y., Fan, X.G.(2014) PLoS One 9: e106225-e106225
- PubMed: 25197973
- DOI: https://doi.org/10.1371/journal.pone.0106225
- Primary Citation of Related Structures:
4U5J - PubMed Abstract:
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.
Organizational Affiliation:
Department of Infectious Diseases & Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan, China.
