4JX7

Crystal structure of Pim1 kinase in complex with inhibitor 2-[(trans-4-aminocyclohexyl)amino]-4-{[3-(trifluoromethyl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one

4JX7 の概要

• エントリーDOI: 10.2210/pdb4jx7/pdb
• 関連するPDBエントリー: 4JX3
• 分子名称: Serine/threonine-protein kinase pim-1, PIM1 consensus peptide, 2-[(trans-4-aminocyclohexyl)amino]-4-{[3-(trifluoromethyl)phenyl]amino}pyrido[4,3-d]pyrimidin-5(6H)-one, ... (4 entities in total)
• 機能のキーワード: serine/threonine-protein kinases, atp binding, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 39304.68

構造登録者

Lee, S.J.,Han, B.G.,Cho, J.W.,Choi, J.S.,Lee, J.K.,Song, H.J.,Koh, J.S.,Lee, B.I. (登録日: 2013-03-27, 公開日: 2013-08-28, 最終更新日: 2023-09-20)

主引用文献

Lee, S.J.,Han, B.G.,Cho, J.W.,Choi, J.S.,Lee, J.,Song, H.J.,Koh, J.S.,Lee, B.I.
Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode.
Plos One, 8:e70358-e70358, 2013

PubMed Abstract: Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (±14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O-068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor.

PubMed: 23936194
DOI: 10.1371/journal.pone.0070358

実験手法

X-RAY DIFFRACTION (2.4 Å)