The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein

Smith, Kathrine J, Carter, Paul S, Bridges, Angela, Horrocks, Pete, Lewis, Ceri, Pettman, Gary, Clarke, Andrew, Brown, Murray, Hughes, Jane, Wilkinson, Marc, Bax, Benjamin ORCID: https://orcid.org/0000-0003-1940-3785 and Reith, Alastair 2004. The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein. Structure 12 (6) , pp. 1067-1077. 10.1016/j.str.2004.02.040

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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 Å 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 β sheet on the N lobe of the kinase domain. The three β strands come from residues at the N terminus of the kinase domain, what would be the αB helix in the active conformation, and the activation loop. The new three-stranded β sheet occupies a position equivalent to the N terminus of the αC helix in active protein kinases.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Elsevier (Cell Press)
ISSN:	0969-2126
Date of Acceptance:	12 February 2004
Last Modified:	23 Oct 2022 14:03
URI:	https://orca.cardiff.ac.uk/id/eprint/112633

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