6NPZ

Crystal structure of Akt1 (aa 123-480) kinase with a bisubstrate

「6C0I」から置き換えられました

6NPZ の概要

• エントリーDOI: 10.2210/pdb6npz/pdb
• 関連するPDBエントリー: 6BUU
• 分子名称: RAC-alpha serine/threonine-protein kinase, bisubstrate, MANGANESE (II) ION, ... (7 entities in total)
• 機能のキーワード: akt1, rac-alpha serine/theronine-protein kinase, kinase, bisubstrate, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 86885.74

構造登録者

Chu, N.,Cole, P.A.,Gabelli, S.B. (登録日: 2019-01-18, 公開日: 2019-01-30, 最終更新日: 2024-10-16)

主引用文献

Chu, N.,Salguero, A.L.,Liu, A.Z.,Chen, Z.,Dempsey, D.R.,Ficarro, S.B.,Alexander, W.M.,Marto, J.A.,Li, Y.,Amzel, L.M.,Gabelli, S.B.,Cole, P.A.
Akt Kinase Activation Mechanisms Revealed Using Protein Semisynthesis.
Cell, 174:897-907.e14, 2018

PubMed Abstract: Akt is a critical protein kinase that drives cancer proliferation, modulates metabolism, and is activated by C-terminal phosphorylation. The current structural model for Akt activation by C-terminal phosphorylation has centered on intramolecular interactions between the C-terminal tail and the N lobe of the kinase domain. Here, we employ expressed protein ligation to produce site-specifically phosphorylated forms of purified Akt1 that are well suited for mechanistic analysis. Using biochemical, crystallographic, and cellular approaches, we determine that pSer473-Akt activation is driven by an intramolecular interaction between the C-tail and the pleckstrin homology (PH)-kinase domain linker that relieves PH domain-mediated Akt1 autoinhibition. Moreover, dual phosphorylation at Ser477/Thr479 activates Akt1 through a different allosteric mechanism via an apparent activation loop interaction that reduces autoinhibition by the PH domain and weakens PIP3 affinity. These results provide a new framework for understanding how Akt is controlled in cell signaling and suggest distinct functions for differentially modified Akt forms.

PubMed: 30078705
DOI: 10.1016/j.cell.2018.07.003

実験手法

X-RAY DIFFRACTION (2.12 Å)