7MYX

Crystal structure of the PH domain (R86A) of Akt1

7MYX の概要

• エントリーDOI: 10.2210/pdb7myx/pdb
• 分子名称: RAC-alpha serine/threonine-protein kinase (2 entities in total)
• 機能のキーワード: kinase, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14456.34

構造登録者

Bae, H.,Park, E.,Cole, P.A.,Eck, M.J. (登録日: 2021-05-22, 公開日: 2022-11-09, 最終更新日: 2023-10-18)

主引用文献

Bae, H.,Viennet, T.,Park, E.,Chu, N.,Salguero, A.,Eck, M.J.,Arthanari, H.,Cole, P.A.
PH domain-mediated autoinhibition and oncogenic activation of Akt.
Elife, 11:-, 2022

PubMed Abstract: Akt is a Ser/Thr protein kinase that plays a central role in metabolism and cancer. Regulation of Akt's activity involves an autoinhibitory intramolecular interaction between its pleckstrin homology (PH) domain and its kinase domain that can be relieved by C-tail phosphorylation. PH domain mutant E17K Akt is a well-established oncogene. Previously, we reported that the conformation of autoinhibited Akt may be shifted by small molecule allosteric inhibitors limiting the mechanistic insights from existing X-ray structures that have relied on such compounds (Chu et al., 2020). Here, we discover unexpectedly that a single mutation R86A Akt exhibits intensified autoinhibitory features with enhanced PH domain-kinase domain affinity. Structural and biochemical analysis uncovers the importance of a key interaction network involving Arg86, Glu17, and Tyr18 that controls Akt conformation and activity. Our studies also shed light on the molecular basis for E17K Akt activation as an oncogenic driver.

PubMed: 35968932
DOI: 10.7554/eLife.80148

実験手法

X-RAY DIFFRACTION (1.39 Å)