Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor.
BACKGROUND
The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2.


RESULTS
Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases.


CONCLUSIONS
The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors.


BACKGROUND
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University of Oxford, Structural Genomics Consortium, Oxford, United Kingdom.
Alex N
AN
Bullock
Santina
S
Russo
Ann
A
Amos
Nicholas
N
Pagano
Howard
H
Bregman
Judit E
JE
Debreczeni
Wen Hwa
WH
Lee
Frank
F
von Delft
Eric
E
Meggers
Stefan
S
Knapp
D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D011487:Protein Conformation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*; D019311:Staurosporine / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D012428:Ruthenium; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D019311:Staurosporine