3UMX

Crystal structure of Pim1 kinase in complex with inhibitor (Z)-2-[(1H-indol-3-yl)methylene]-7-(azepan-1-ylmethyl)-6-hydroxybenzofuran-3(2H)-one

3UMX の概要

• エントリーDOI: 10.2210/pdb3umx/pdb
• 関連するPDBエントリー: 3UIX 3UMW
• 分子名称: Proto-oncogene serine/threonine-protein kinase pim-1, (2Z)-7-(azepan-1-ylmethyl)-6-hydroxy-2-(1H-indol-3-ylmethylidene)-1-benzofuran-3(2H)-one, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: pim-1, kinase, p-loop, kinase inhibitor, rational drug design, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens
• 細胞内の位置: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34672.25

構造登録者

Parker, L.J.,Handa, N.,Yokoyama, S. (登録日: 2011-11-15, 公開日: 2012-08-08, 最終更新日: 2023-11-01)

主引用文献

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

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: 22869110
DOI: 10.1107/S1744309112027108

実験手法

X-RAY DIFFRACTION (2.55 Å)