3UIX
Crystal structure of Pim1 kinase in complex with small molecule inhibitor
Summary for 3UIX
| Entry DOI | 10.2210/pdb3uix/pdb |
| Descriptor | Proto-oncogene serine/threonine-protein kinase pim-1, 2-{4-[(3-aminopropyl)amino]quinazolin-2-yl}phenol, CHLORIDE ION, ... (7 entities in total) |
| Functional Keywords | pim-1, leukemia cell lethality, substrate-peptide-binding residue, fluorescent correlation spectroscopy, inhibitor complex, in silico screening, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens |
| Cellular location | Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309 |
| Total number of polymer chains | 1 |
| Total formula weight | 34781.22 |
| Authors | Parker, L.J. (deposition date: 2011-11-06, release date: 2012-04-11, Last modification date: 2023-11-01) |
| Primary citation | Tsuganezawa, K.,Watanabe, H.,Parker, L.,Yuki, H.,Taruya, S.,Nakagawa, Y.,Kamei, D.,Mori, M.,Ogawa, N.,Tomabechi, Y.,Handa, N.,Honma, T.,Yokoyama, S.,Kojima, H.,Okabe, T.,Nagano, T.,Tanaka, A. A novel pim-1 kinase inhibitor targeting residues that bind the substrate Peptide. J.Mol.Biol., 417:240-252, 2012 Cited by PubMed Abstract: A new screening method using fluorescent correlation spectroscopy was developed to select kinase inhibitors that competitively inhibit the binding of a fluorescently labeled substrate peptide. Using the method, among approximately 700 candidate compounds selected by virtual screening, we identified a novel Pim-1 kinase inhibitor targeting its peptide binding residues. X-ray crystal analysis of the complex structure of Pim-1 with the inhibitor indicated that the inhibitor actually binds to the ATP-binding site and also forms direct interactions with residues (Asp128 and Glu171) that bind the substrate peptide. These interactions, which cause small side-chain movements, seem to affect the binding ability of the fluorescently labeled substrate. The compound inhibited Pim-1 kinase in vitro, with an IC(50) value of 150 nM. Treatment of cultured leukemia cells with the compound reduced the amount of p21 and increased the amount of p27, due to Pim-1 inhibition, and then triggered apoptosis after cell-cycle arrest at the G(1)/S phase. This screening method may be widely applicable for the identification of various new Pim-1 kinase inhibitors targeting the residues that bind the substrate peptide. PubMed: 22306408DOI: 10.1016/j.jmb.2012.01.036 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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