Capturing Autoinhibited PDK1 Reveals the Linker's Regulatory Role, Informing Innovative Inhibitor Design.

ABSTRACT: PDK1 is crucial for PI3K/AKT/mTOR and Ras/MAPK cancer signaling. It phosphorylates AKT in a PIP₃-dependent but S6K, SGK, and RSK kinases in a PIP₃-independent manner. Unlike its substrates, its autoinhibited monomeric state has been unclear, likely due to its low population time, and phosphorylation in the absence of PIP₃ has been puzzling too. Here, guided by experimental data, we constructed models and performed all-atom molecular dynamics simulations. In the autoinhibited PDK1 conformation that resembles autoinhibited AKT, binding of the linker between the kinase and PH domains to the PIF-binding pocket promotes the formation of the Glu¹³⁰-Lys¹¹¹ salt bridge and weakens the association of the kinase domain with the PH domain, shifti

SUBMITTER: Xu L 

PROVIDER: S-EPMC12101721 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature