The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein.
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.
Discovery Research, GlaxoSmithKline, Third Ave, Harlow, Essex, CM19 5AW, United Kingdom. katherine_j_smith@gsk.com
Kathrine J
KJ
Smith
Paul S
PS
Carter
Angela
A
Bridges
Pete
P
Horrocks
Ceri
C
Lewis
Gary
G
Pettman
Andrew
A
Clarke
Murray
M
Brown
Jane
J
Hughes
Marc
M
Wilkinson
Benjamin
B
Bax
Alastair
A
Reith
D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D007313:Insecta; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D048051:p38 Mitogen-Activated Protein Kinases
D000255:Adenosine Triphosphate; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases