5O11

Crystal structure of PIM1 kinase in complex with small-molecule inhibitor

Summary for 5O11

• Entry DOI: 10.2210/pdb5o11/pdb
• Descriptor: Serine/threonine-protein kinase pim-1, 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid, IMIDAZOLE, ... (6 entities in total)
• Functional Keywords: kinase, cx-4945, pim1, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 1
• Total formula weight: 35172.49

Authors

Bogusz, J.,Dubin, G. (deposition date: 2017-05-17, release date: 2017-11-01, Last modification date: 2024-11-13)

Primary citation

Bogusz, J.,Zrubek, K.,Rembacz, K.P.,Grudnik, P.,Golik, P.,Romanowska, M.,Wladyka, B.,Dubin, G.
Structural analysis of PIM1 kinase complexes with ATP-competitive inhibitors.
Sci Rep, 7:13399-13399, 2017

PubMed Abstract: PIM1 is an oncogenic kinase overexpressed in a number of cancers where it correlates with poor prognosis. Several studies demonstrated that inhibition of PIM1 activity is an attractive strategy in fighting overexpressing cancers, while distinct structural features of ATP binding pocket make PIM1 an inviting target for the design of selective inhibitors. To facilitate development of specific PIM1 inhibitors, in this study we report three crystal structures of ATP-competitive inhibitors at the ATP binding pocket of PIM1. Two of the reported structures (CX-4945 and Ro-3306) explain the off-target effect on PIM1 of respectively casein kinase 2 and cyclin-dependent kinase 1 dedicated inhibitors. In turn, the structure with CX-6258 demonstrates a binding mode of a potent, selective inhibitor of PIM1, PIM2, PIM3 and Flt-3 kinases. The consequences of our findings for future inhibitor development are discussed.

PubMed: 29042609
DOI: 10.1038/s41598-017-13557-z

Experimental method

X-RAY DIFFRACTION (2.4 Å)