PIM2: Human Proviral Integration Site for MuLV
PDB Code: 2IWI
The Pim kinase family includes three constitutively active serine/threonine kinases (Pim-1, -2, and -3) that function as important mediators of cytokine signaling pathways in hematopoietic cells. Pim-2 plays an important role in tumour progression and is overexpressed in human chronic lymphocytic leukemia and non-Hodgkin lymphomas. Pim-2 prosurvival signaling can protect cancer cells from apotosis and confers resistance to rapamycin. Substrates include the pro-apoptotic protein BAD, which is phosphorylated on serine 112, thus preventing BAD-Bcl-x L interaction and reversing Bad-induced cell death. Pim-2 also phosphorylates SOCS-1 which stabilizes the protein enabling negative feedback of the Jak/STAT pathway.
The Pim kinases are distinguished by a unique hinge-region sequence ERPXPX which removes the +3 hydrogen bond donor and provides potential for the design of specific inhibitors. Pim-2 was crystallized with the ruthenium half-sandwich complex (R)- 5 which is a kinetically-inert metal complex based on the inhibitor staurosporine. Such metal complexes extend the small molecule chemical space previously explored by purely organic scaffolds and produces highly potent inhibitors of the Pim kinases.
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