Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3β

Human tau‐protein kinase I (TPK I; also known as glycogen synthase kinase 3β; GSK3β) is a serine/threonine protein kinase that participates in Alzheimer's disease. Here, binary complex structures of full‐length TPK I/GSK3β with the ATP analogues ADP and AMPPNP solved by the X‐ray diffraction method at 2.1 and 1.8 Å resolution, respectively, are reported. TPK I/GSK3β is composed of three domains: an N‐terminal domain consisting of a closed β‐barrel structure, a C‐terminal domain containing a `kinase fold' structure and a small extra‐domain subsequent to the C‐terminal domain. The catalytic site is between the two major domains and has an ATP‐analogue molecule in its ATP‐binding site. The adenine ring is buried in the hydrophobic pocket and interacts specifically with the main‐chain atoms of the hinge loop. The overall structure and substrate‐binding residues are similar to those observed in other Ser/Thr protein kinases, while Arg141 (which is not conserved among other Ser/Thr protein kinases) is one of the key residues for specific ATP/ADP recognition by TPK I/GSK3β. No residues are phosphorylated, while the orientation of the activation loop in TPK I/GSK3β is similar to that in phosphorylated CDK2 and ERK2, suggesting that TPK I/GSK3β falls into a conformation that enables it to be constitutively active.