title: Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme.
abstract: MAP KAP kinase 2 (MK2), a Ser/Thr kinase, plays a crucial role in the inflammatory process. We have determined the crystal structures of a catalytically active C-terminal deletion form of human MK2, residues 41-364, in complex with staurosporine at 2.7 A and with ADP at 3.2 A, revealing overall structural similarity with other Ser/Thr kinases. Kinetic analysis reveals that the K(m) for ATP is very similar for MK2 41-364 and p38-activated MK2 41-400. Conversely, the catalytic rate and binding for peptide substrate are dramatically reduced in MK2 41-364. However, phosphorylation of MK2 41-364 by p38 restores the V(max) and K(m) for peptide substrate to values comparable to those seen in p38-activated MK2 41-400, suggesting a mechanism for regulation of enzyme activity.
authors.affiliation: Department of Biological Chemistry, Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140, USA. kunderwood@wyeth.com
authors.forename: Kathryn W
authors.initials: KW
authors.lastname: Underwood
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Parris
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Federico
authors.forename: Lidia
authors.initials: L
authors.lastname: Mosyak
authors.forename: Robert M
authors.initials: RM
authors.lastname: Czerwinski
authors.forename: Tania
authors.initials: T
authors.lastname: Shane
authors.forename: Meggin
authors.initials: M
authors.lastname: Taylor
authors.forename: Kristine
authors.initials: K
authors.lastname: Svenson
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Chu-Lai
authors.initials: CL
authors.lastname: Hsiao
authors.forename: Scott
authors.initials: S
authors.lastname: Wolfrom
authors.forename: Michelle
authors.initials: M
authors.lastname: Maguire
authors.forename: Karl
authors.initials: K
authors.lastname: Malakian
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Telliez
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Kriz
authors.forename: Jasbir
authors.initials: J
authors.lastname: Seehra
authors.forename: William S
authors.initials: WS
authors.lastname: Somers
authors.forename: Mark L
authors.initials: ML
authors.lastname: Stahl
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D019311:Staurosporine / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000244:Adenosine Diphosphate; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2