1UNG

Structural mechanism for the inhibition of CDK5-p25 by roscovitine, aloisine and indirubin.

1UNG の概要

• エントリーDOI: 10.2210/pdb1ung/pdb
• 関連するPDBエントリー: 1H4L 1LFR 1UNH 1UNL
• 分子名称: CELL DIVISION PROTEIN KINASE 5, CYCLIN-DEPENDENT KINASE 5 ACTIVATOR 1, 6-PHENYL[5H]PYRROLO[2,3-B]PYRAZINE, ... (4 entities in total)
• 機能のキーワード: cell cycle, complex(kinase-activator), inhibitors, neurodegenerative diseases
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Cytoplasm (By similarity): Q00535; Cyclin-dependent kinase 5 activator 1, p35: Cell membrane; Lipid-anchor; Cytoplasmic side (Probable). Cyclin-dependent kinase 5 activator 1, p25: Nucleus: Q15078
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 113634.96

構造登録者

Mapelli, M.,Crovace, C.,Massimiliano, L.,Musacchio, A. (登録日: 2003-09-10, 公開日: 2004-11-10, 最終更新日: 2023-12-13)

主引用文献

Mapelli, M.,Massimilinao, L.,Crovace, C.,Seeliger, M.A.,Tsai, L.-H.,Meijer, L.,Musacchio, A.
Mechanism of Cdk5/P25 Binding by Cdk Inhibitors
J.Med.Chem., 48:671-, 2005

PubMed Abstract: The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 A, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.

PubMed: 15689152
DOI: 10.1021/JM049323M

実験手法

X-RAY DIFFRACTION (2.3 Å)