Summary for 6NPZ
| Entry DOI | 10.2210/pdb6npz/pdb |
| Related | 6BUU |
| Descriptor | RAC-alpha serine/threonine-protein kinase, bisubstrate, MANGANESE (II) ION, ... (7 entities in total) |
| Functional Keywords | akt1, rac-alpha serine/theronine-protein kinase, kinase, bisubstrate, transferase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 86885.74 |
| Authors | Chu, N.,Cole, P.A.,Gabelli, S.B. (deposition date: 2019-01-18, release date: 2019-01-30, Last modification date: 2024-10-16) |
| 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 Cited by 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: 30078705DOI: 10.1016/j.cell.2018.07.003 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.12 Å) |
Structure validation
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