Subdomain VIII of Cyclin-Dependent Kinase 2


Subdomain VIII is made up of L12 which includes residues 158-175. It is important because it contains the T-loop, which is the activation region of the molecule. (Part of the T-loop is in subdomain VII, as it runs from residues 152-170.) It is called the T-loop because Thr160 is the important conserved residue that gets phosphorylated by MO15(CAK) to completely activate Cdk2. Thr160, which is located on the apex of the T-loop, is 33% solvent accessible, but its hydroxyl group is not open to solvent due to its orientation toward the glycine-rich loop. The T-loop blocks the protein substrate binding site of the free kinase, acting as an auto-inhibitor of the kinase. When cyclin A binds to Cdk2, major conformational and positional changes take place in the T-loop, opening up the catalytic cleft. The helices alpha-1, alpha-2 and alpha-3 of cyclin A bind the T-loop at its N-terminal end. Residues from Cdk2 make van der Waals interactions as well as hydrogen bonds with residues from cyclin.

Residues 156-162 are highly dynamic, as evident from the quality of their electron density. This part of the loop may be flexible as well.