Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002.

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Jacobs MD, Black J, Futer O, Swenson L, Hare B, Fleming M, Saxena K

Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002.

J Biol Chem. 2005 Apr 8;280(14):13728-34. Epub 2005 Jan 17.

PubMed ID

15657054 [ View in PubMed

]

Abstract

Pim-1 is an oncogene-encoded serine/threonine kinase primarily expressed in hematopoietic and germ cell lines. Pim-1 kinase was originally identified in Maloney murine leukemia virus-induced T-cell lymphomas and is associated with multiple cellular functions such as proliferation, survival, differentiation, apoptosis, and tumorigenesis (Wang, Z., Bhattacharya, N., Weaver, M., Petersen, K., Meyer, M., Gapter, L., and Magnuson, N. S. (2001) J. Vet. Sci. 2, 167-179). The crystal structures of Pim-1 complexed with staurosporine and adenosine were determined. Although a typical two-domain serine/threonine protein kinase fold is observed, the inter-domain hinge region is unusual in both sequence and conformation; a two-residue insertion causes the hinge to bulge away from the ATP-binding pocket, and a proline residue in the hinge removes a conserved main chain hydrogen bond donor. Without this hydrogen bond, van der Waals interactions with the hinge serve to position the ligand. The hinge region of Pim-1 resembles that of phosphatidylinositol 3-kinase more closely than it does other protein kinases. Although the phosphatidylinositol 3-kinase inhibitor LY294002 also inhibits Pim-1, the structure of the LY294002.Pim-1 complex reveals a new binding mode that may be general for Ser/Thr kinases.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Serine/threonine-protein kinase pim-1	P11309	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bisindolylmaleimide I	Serine/threonine-protein kinase pim-1	IC 50 (nM)	150	7.6	30	Details
LY-294002	Serine/threonine-protein kinase pim-1	IC 50 (nM)	4000	7.6	30	Details
Staurosporine	Serine/threonine-protein kinase pim-1	IC 50 (nM)	10	7.6	30	Details