6BUU

Crystal structure of AKT1 (aa 144-480) with a bisubstrate

Summary for 6BUU

• Entry DOI: 10.2210/pdb6buu/pdb
• Related: 6C01
• Descriptor: RAC-alpha serine/threonine-protein kinase, GLY-ARG-PRO-ARG-THR-THR-ZXW-PHE-ALA-GLU, SULFATE ION, ... (5 entities in total)
• Functional Keywords: akt1, rac-alpha serine/theronine-protein kinase, kinase, phosphorylated tail, semi-synthesis, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 82053.92

Authors

Chu, N.,Gabelli, S.B.,Cole, P.A. (deposition date: 2017-12-11, release date: 2018-08-22, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)