4U5J

C-Src in complex with Ruxolitinib

Summary for 4U5J

• Entry DOI: 10.2210/pdb4u5j/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (3 entities in total)
• Functional Keywords: c-src, ruxolitinib, kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Gallus gallus (Chicken)
• Cellular location: Cell membrane : P00523
• Total number of polymer chains: 2
• Total formula weight: 66066.02

Authors

Chen, Y.,Duan, Y.,Chen, L. (deposition date: 2014-07-25, release date: 2014-09-17, Last modification date: 2024-06-26)

Primary citation

Duan, Y.,Chen, L.,Chen, Y.,Fan, X.G.
c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation
Plos One, 9:e106225-e106225, 2014

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.

PubMed: 25197973
DOI: 10.1371/journal.pone.0106225

Experimental method

X-RAY DIFFRACTION (2.26 Å)