2zv2
Crystal structure of human calcium/calmodulin-dependent protein kinase kinase 2, beta, CaMKK2 kinase domain in complex with STO-609Crystal structure of human calcium/calmodulin-dependent protein kinase kinase 2, beta, CaMKK2 kinase domain in complex with STO-609
Structural highlights
FunctionKKCC2_HUMAN Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin-binding domain are inactive. Efficiently phosphorylates 5'-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching.[1] [2] [3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCa(2+)/calmodulin (CaM)-dependent protein kinase (CaMK) kinase (CaMKK) is a member of the CaMK cascade that mediates the response to intracellular Ca(2+) elevation. CaMKK phosphorylates and activates CaMKI and CaMKIV, which directly activate transcription factors. In this study, we determined the 2.4 A crystal structure of the catalytic kinase domain (KD) of the human CaMKK beta isoform complexed with its selective inhibitor, STO-609. The structure revealed that CaMKKbeta lacks the alphaD helix and that the equivalent region displays a hydrophobic molecular surface, which may reflect its unique substrate recognition and autoinhibition. Although CaMKKbeta lacks the activation-loop phosphorylation site, the activation loop is folded in an active-state conformation, which is stabilized by a number of interactions between amino acid residues conserved among the CaMKK isoforms. An in vitro analysis of the kinase activity confirmed the intrinsic activity of the CaMKKbeta KD. Structure and sequence analyses of the STO-609-binding site revealed amino-acid replacements that may affect the inhibitor binding. Indeed, mutagenesis demonstrated that the CaMKKbeta residue Pro274, which replaces the conserved acidic residue of other protein kinases, is an important determinant for the selective inhibition by STO-609. Therefore, the present structure provides a molecular basis for clarifying the known biochemical properties of CaMKKbeta, and for designing novel inhibitors targeting CaMKKbeta and the related protein kinases. Crystal structure of the CA2+/calmodulin-dependent protein kinase kinase in complex with the inhibitor STO-609.,Kukimoto-Niino M, Yoshikawa S, Takagi T, Ohsawa N, Tomabechi Y, Terada T, Shirouzu M, Suzuki A, Lee S, Yamauchi T, Okada-Iwabu M, Iwabu M, Kadowaki T, Minokoshi Y, Yokoyama S J Biol Chem. 2011 Apr 19. PMID:21504895[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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