5UQ2

Crystal structure of human Cdk2-Spy1 complex

5UQ2 の概要

• エントリーDOI: 10.2210/pdb5uq2/pdb
• 関連するPDBエントリー: 5UQ1 5UQ3
• 分子名称: Cyclin-dependent kinase 2, Speedy protein A (3 entities in total)
• 機能のキーワード: phosphotransferase, protein kinase, cell cycle regulation, transferase-cell cycle complex, transferase/cell cycle
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941; Nucleus : Q5MJ70
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53622.05

構造登録者

McGrath, D.A.,Tripathi, S.M.,Rubin, S.M. (登録日: 2017-02-06, 公開日: 2017-07-05, 最終更新日: 2024-10-23)

主引用文献

McGrath, D.A.,Fifield, B.A.,Marceau, A.H.,Tripathi, S.,Porter, L.A.,Rubin, S.M.
Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins.
EMBO J., 36:2251-2262, 2017

PubMed Abstract: Cyclin-dependent kinases (Cdks) are principal drivers of cell division and are an important therapeutic target to inhibit aberrant proliferation. Cdk enzymatic activity is tightly controlled through cyclin interactions, posttranslational modifications, and binding of inhibitors such as the p27 tumor suppressor protein. Spy1/RINGO (Spy1) proteins bind and activate Cdk but are resistant to canonical regulatory mechanisms that establish cell-cycle checkpoints. Cancer cells exploit Spy1 to stimulate proliferation through inappropriate activation of Cdks, yet the mechanism is unknown. We have determined crystal structures of the Cdk2-Spy1 and p27-Cdk2-Spy1 complexes that reveal how Spy1 activates Cdk. We find that Spy1 confers structural changes to Cdk2 that obviate the requirement of Cdk activation loop phosphorylation. Spy1 lacks the cyclin-binding site that mediates p27 and substrate affinity, explaining why Cdk-Spy1 is poorly inhibited by p27 and lacks specificity for substrates with cyclin-docking sites. We identify mutations in Spy1 that ablate its ability to activate Cdk2 and to proliferate cells. Our structural description of Spy1 provides important mechanistic insights that may be utilized for targeting upregulated Spy1 in cancer.

PubMed: 28666995
DOI: 10.15252/embj.201796905

実験手法

X-RAY DIFFRACTION (2.7 Å)