CAMK4: Human calcium/calmodulin-dependent protein kinase IV in complex with K00546
PDB Code: 2W4O
The serine threonine kinase CAMK4 is highly expressed in the brain, testis and cells of the immune system. In the brain, this kinase is required for the consolidation/retention of hippocampus-dependent long-term memory, contextual and auditory fear memory and regulation of anxiety-like behaviour. Mouse models have revealed its role in spermiogenesis and sperm motility CAMK4 also plays a major role in the immune system by regulating the selection threshold of double positive thymocytes in the thymus. Regulation of maintenance of hemtopoietic progenitor cells and dendritic cells requires CAMK4 to prevent inappropriate proliferation. Recently, it has also been shown that osteoclasts differentiation and function is dependent on CAMK4.
The overall domain organization of CAMK family members is similar: an N-terminal catalytic domain is followed by a regulatory domain that contains an autoinhibitory region containing a calmodulin (CaM) binding site. CAMK4 is activated by a three step activation process: Increase in intracellular Ca2+ causes CAMK4 binding to Ca2+/CaM and results in CAMK4 phosphorylation at Thr196 by CaMKK. Phosphorylation at this site releases the regulatory Ca2+/CaM binding helix from the kinase substrate binding site. This activation step is sufficient to cause autophosphorylation at Ser11 and Ser12 which is required to further relieve the autoinhibition mediated by the N-terminus. Phosphorylation of Thr196 renders CAMK4 independent of Ca2+/CaM. However, inactivation may occur by dephosphorylation of Thr196 by the CAMK4 associated phosphatases PP2A.
We have solved the structure of CAMK4 catalytic domain in complex with an ATP competitive inhibitor (4-Amino-3(4sulfamoyl-phenylamino) triazole-1-carbothioic acid (2,6-difluoro-phenyl)-amide) at 2.4 Å resolution in its inactive unphosphorylated state.
K00546 ((4-Amino-3(4sulfamoyl-phenylamino)triazole-1-carbothioic acid (2,6-difluoro-phenyl)-amide))*
*(The SGC would like to thank the laboratory of K. Shokat at the Department of Cellular and Molecular Pharmacology University of California, San Francisco for providing this inhibitor)
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