4ENY
Crystal Structure of Pim-1 kinase in complex with (2E,5Z)-2-(2-chlorophenylimino)-5-(4-hydroxy-3-methoxybenzylidene)thiazolidin-4-one
Summary for 4ENY
| Entry DOI | 10.2210/pdb4eny/pdb |
| Related | 3UIX 3UMW 3UMX 4ENX |
| Descriptor | Serine/threonine-protein kinase pim-1, DIMETHYL SULFOXIDE, GLYCEROL, ... (6 entities in total) |
| Functional Keywords | pim-1 kinase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309 |
| Total number of polymer chains | 1 |
| Total formula weight | 34813.74 |
| Authors | Parker, L.J.,Handa, N.,Yokoyama, S. (deposition date: 2012-04-13, release date: 2012-08-08, Last modification date: 2023-11-08) |
| Primary citation | Parker, L.J.,Watanabe, H.,Tsuganezawa, K.,Tomabechi, Y.,Handa, N.,Shirouzu, M.,Yuki, H.,Honma, T.,Ogawa, N.,Nagano, T.,Yokoyama, S.,Tanaka, A. Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor Acta Crystallogr.,Sect.F, 68:860-866, 2012 Cited by PubMed Abstract: The serine/threonine kinase Pim-1 is emerging as a promising target for cancer therapeutics. Much attention has recently been focused on identifying potential Pim-1 inhibitor candidates for the treatment of haematopoietic malignancies. The outcome of a rational drug-design project has recently been reported [Nakano et al. (2012), J. Med. Chem. 55, 5151-5156]. The report described the process of optimization of the structure-activity relationship and detailed from a medicinal chemistry perspective the development of a low-potency and nonselective compound initially identified from in silico screening into a potent, selective and metabolically stable Pim-1 inhibitor. Here, the structures of the initial in silico hits are reported and the noteworthy features of the Pim-1 complex structures are described. A particular focus was placed on the rearrangement of the glycine-rich P-loop region that was observed for one of the initial compounds, (Z)-7-(azepan-1-ylmethyl)-2-[(1H-indol-3-yl)methylidene]-6-hydroxy-1-benzofuran-3(2H)-one (compound 1), and was also found in all further derivatives. This novel P-loop conformation, which appears to be stabilized by an additional interaction with the β3 strand located above the binding site, is not usually observed in Pim-1 structures. PubMed: 22869110DOI: 10.1107/S1744309112027108 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.801 Å) |
Structure validation
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