title: c-Src binds to the cancer drug Ruxolitinib with an active conformation.
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.
authors.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.
authors.forename: Yankun
authors.initials: Y
authors.lastname: Duan
authors.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; Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.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; Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Yongheng
authors.initials: Y
authors.lastname: Chen
authors.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.
authors.forename: Xue-gong
authors.initials: XG
authors.lastname: Fan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000378:metabolism*; D001665:Binding Sites; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009570:Nitriles; D015688:Oncogene Protein pp60(v-src) / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011720:Pyrazoles / Q000378:metabolism*; D011743:Pyrimidines; D017386:Sequence Homology, Amino Acid
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D000255:Adenosine Triphosphate; D015688:Oncogene Protein pp60(v-src)