The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein |
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Authors: | Smith Kathrine J Carter Paul S Bridges Angela Horrocks Pete Lewis Ceri Pettman Gary Clarke Andrew Brown Murray Hughes Jane Wilkinson Marc Bax Benjamin Reith Alastair |
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Affiliation: | Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, United Kingdom. katherine_j_smith@gsk.com |
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Abstract: | 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. |
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