The Structure of MSK1 Reveals a Novel Autoinhibitory Conformation for a Dual Kinase Protein

• DOI: 10.1016/j.str.2004.02.040
• Publication Date: 2004-06-09T20:56:45Z
• Authors: Kathrine J Smith; Paul S Carter; Angela Bridges; Pete Horrocks; Ceri Lewis; Gary Pettman; Andrew Clarke; Murray Brown; Jane Hughes; Marc Wilkinson; Benjamin Bax; Alastair Reith
• Keywords: c-Raf; MAP2K7; Protein kinase domain; Cyclin-dependent kinase 9; Transferase

Mitogen and stress-activated kinase-1 (MSK1) is a serine/threonine protein kinase that is activated by either p38 or p42ERK MAPKs in response to stress or mitogenic extracellular stimuli. MSK1 belongs to a family of protein kinases that contain two distinct kinase domains in one polypeptide chain. We report the 1.8 A crystal structure of the N-terminal kinase domain of MSK1. The crystal structure reveals a unique inactive conformation with the ATP binding site blocked by the nucleotide binding loop. This inactive conformation is stabilized by the formation of a new three-stranded beta sheet on the N lobe of the kinase domain. The three beta strands come from residues at the N terminus of the kinase domain, what would be the alphaB helix in the active conformation, and the activation loop. The new three-stranded beta sheet occupies a position equivalent to the N terminus of the alphaC helix in active protein kinases.