Insights into the Conformational Plasticity of the Protein Kinase Akt1 by Multi‐Lateral Dipolar Spectroscopy

• Published in: Chemistry : a European journal Vol. 29; no. 24; pp. e202203959 - n/a
• Main Authors: Stehle, Juliane, Weisner, Jörn, Eichhorn, Leanne, Rauh, Daniel, Drescher, Malte
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 25.04.2023
• Subjects: AKT protein; AKT1 protein; Apoptosis; Chemistry; DEER; Domains; Electron paramagnetic resonance; Electron spin resonance; Electron Spin Resonance Spectroscopy; EPR spectroscopy; Humans; kinase inhibitors; Kinases; Modulators; multilateration; Mutation; Neoplasms; Protein Serine-Threonine Kinases - genetics; protein structure; Protein-serine/threonine kinase; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Spectroscopy; spin label; protein structure; DEER; kinase inhibitors; multilateration; EPR spectroscopy; spin label
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202203959

The serine/threonine kinase Akt1 is part of the PI3 K/Akt pathway and plays a key role in the regulation of various cellular processes such as cell growth, proliferation, and apoptosis. Here, we analyzed the elasticity between the two domains of the kinase Akt1, connected by a flexible linker, recording a wide variety of distance restraints by electron paramagnetic resonance (EPR) spectroscopy. We studied full length Akt1 and the influence of the cancer‐associated mutation E17K. The conformational landscape in the presence of different modulators, like different types of inhibitors and membranes was presented, revealing a tuned flexibility between the two domains, dependent on the bound molecule. The conformational flexibility between the pleckstrin homology (PH) and kinase domain of the kinase Akt1 was investigated using multilateration of double electron resonance spectroscopy (DEER) distance restraints. Detailed structural data of wild‐type Akt1 and the cancer‐associated E17K mutation in the apo and ligand‐bound states are presented, yielding deep insights into the conformational plasticity of Akt1.