2ZV2

Crystal structure of human calcium/calmodulin-dependent protein kinase kinase 2, beta, CaMKK2 kinase domain in complex with STO-609

Summary for 2ZV2

• Entry DOI: 10.2210/pdb2zv2/pdb
• Descriptor: Calcium/calmodulin-dependent protein kinase kinase 2, 7-oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic acid (3 entities in total)
• Functional Keywords: calcium/calmodulin-dependent protein kinase kinase 2, beta, sto-609, camkk2, e.c.2.7.11.17, phosphorylation, ampkk, metabolism, atp-binding, kinase, calmodulin-binding, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase, structural genomics, nppsfa, national project on protein structural and functional analyses, riken structural genomics/proteomics initiative, rsgi, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus (By similarity): Q96RR4
• Total number of polymer chains: 1
• Total formula weight: 33921.95

Authors

Yoshikawa, S.,Kukimoto-niino, M.,Shirouzu, M.,Suzuki, A.,Lee, S.,Minokoshi, Y.,Yokoyama, S.,RIKEN Structural Genomics/Proteomics Initiative (RSGI) (deposition date: 2008-10-31, release date: 2009-11-03, Last modification date: 2023-11-01)

Primary citation

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.
Crystal structure of the Ca2+/calmodulin-dependent protein kinase kinase in complex with the inhibitor STO-609
J.Biol.Chem., 286:22570-22579, 2011

PubMed Abstract: Ca(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 Å crystal structure of the catalytic kinase domain of the human CaMKKβ isoform complexed with its selective inhibitor, STO-609. The structure revealed that CaMKKβ lacks the αD helix and that the equivalent region displays a hydrophobic molecular surface, which may reflect its unique substrate recognition and autoinhibition. Although CaMKKβ 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 CaMKKβ kinase domain. 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 CaMKKβ residue Pro(274), 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 CaMKKβ and for designing novel inhibitors targeting CaMKKβ and the related protein kinases.

PubMed: 21504895
DOI: 10.1074/jbc.M111.251710

Experimental method

X-RAY DIFFRACTION (2.4 Å)