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.
Highlights
Protein kinases catalyze the transfer of a phosphoryl group from adenosine triphosphate (ATP) to serine, threonine or tyrosine residues of its substrate proteins[1]
Ruxolitinib binding to the ATP-binding pocket of c-Src To see how cancer drug Ruxolitinib interacts with a kinase, we determined the X-ray structure of c-Src in complex with Ruxolitinib to a resolution of 2.26 A
The structure of the c-Src is composed of a bi-lobed architecture (Nlobe and C-lobe) that is typical for protein tyrosine kinases
Summary
Protein kinases catalyze the transfer of a phosphoryl group from adenosine triphosphate (ATP) to serine, threonine or tyrosine residues of its substrate proteins[1]. Such posttranslational modifications serve as a mechanism to modulate enzymatic activity or molecular interactions of substrate proteins in response to endogenous and exogenous signals[1]. Protein kinases are therapeutic targets for the treatment of human diseases[3]. A prototypical example, Imatinib, targets BCR-Abl, a constitutively active form of the Abl kinase that leads to chronic myeloid leukemia (CML), and is very successful in the treatment of this disease[4]
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