This research article identifies the structural basis for how the protein kinase mTORC2 selectively recruits and phosphorylates Akt and related AGC family kinases. Researchers utilized expressed protein ligation to create semisynthetic Akt probes, allowing them to trap the transient kinase-substrate interaction for high-resolution cryo-electron microscopy analysis. The study reveals that mTORC2 recognition depends on two distinct long-range docking interfaces—the CRIM domain and the "N-mooring" of the mSin1 subunit—rather than the local amino acid sequence surrounding the phosphorylation site. These findings demonstrate that mTORC2 directly phosphorylates both the Ser473 hydrophobic motif and the Thr450 turn motif through a coordinated conformational change at the plasma membrane. By defining these specific binding surfaces, the authors provide a molecular framework for developing therapeutic inhibitors that selectively target mTORC2 over the closely related mTORC1 complex. This work ultimately clarifies long-standing questions regarding substrate specificity in vital signaling networks associated with cancer and diabetes.

References:

• Taylor M S, Chen M, Hancock M, et al. Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2[J]. Science, 2025: eadv7111.