Pim1, a serine/threonine kinase, is involved in several biological functions 
including cell survival, proliferation, and differentiation. While pim1 has been 
shown to be involved in several hematopoietic cancers, it was also recently 
identified as a target of aberrant somatic hypermutation in diffuse large cell 
lymphoma (DLCL), the most common form of non-Hodgkin's lymphoma. The crystal 
structures of Pim1 in apo form and bound with AMPPNP have been solved and 
several unique features of Pim1 were identified, including the presence of an 
extra beta-hairpin in the N-terminal lobe and an unusual conformation of the 
hinge connecting the two lobes of the enzyme. While the apo Pim1 structure is 
nearly identical with that reported recently, the structure of AMPPNP bound to 
Pim1 is significantly different. Pim1 is unique among protein kinases due to the 
presence of a proline residue at position 123 that precludes the formation of 
the canonical second hydrogen bond between the hinge backbone and the adenine 
moiety of ATP. One crystal structure reported here shows that changing P123 to 
methionine, a common residue that offers the backbone hydrogen bond to ATP, does 
not restore the ATP binding pocket of Pim1 to that of a typical kinase. These 
unique structural features in Pim1 result in novel binding modes of AMP and a 
known kinase inhibitor scaffold, as shown by co-crystallography. In addition, 
the kinase activities of five Pim1 mutants identified in DLCL patients have been 
determined. In each case, the observed effects on kinase activity are consistent 
with the predicted consequences of the mutation on the Pim1 structure. Finally, 
70 co-crystal structures of low molecular mass, low-affinity compounds with Pim1 
have been solved in order to identify novel chemical classes as potential Pim1 
inhibitors. Based on the structural information, opportunities for optimization 
of one specific example are discussed.