NDLI: A Single Amino Acid Difference between α and β Ca2+/Calmodulin-dependent Protein Kinase Kinase Dictates Sensitivity to the Specific Inhibitor, STO-609

Content Provider	Journal of Biological Chemistry (JBC)
Author	Tokumitsu, Hiroshi Inuzuka, Hiroyuki Ishikawa, Yumi Kobayashi, Ryoji
Abstract	We recently developed STO-609, a selective inhibitor of Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK), and we demonstrated that CaM-KKβ is more sensitive to STO-609 than the CaM-KKα isoform (Tokumitsu H., Inuzuka H., Ishikawa Y., Ikeda M., Saji I., and Kobayashi R. (2002) J. Biol. Chem. 277, 15813–15818). By using catalytic chimera and point mutants of both isoforms, we demonstrated that Val269 in CaM-KKβ/Leu233 in CaM-KKα confers a distinct sensitivity (∼10-fold) to STO-609 on CaM-KK isoforms. Various mutations of Val269 in CaM-KKβ indicate that substitution by hydrophobic residues with bulky side chains significantly decreases drug sensitivity and that the V269F mutant is the most effective drug-resistant enzyme (∼80-fold higher IC50 value). These findings are consistent with a result obtained with a full-length mutant expressed in COS-7 cells. Furthermore, suppression of CaM-KK-mediated CaM-KIV activation in transfected HeLa cells by STO-609 treatment was completely abolished by the co-expression of the CaM-KKβ V269F mutant. Based on the results that the distinct sensitivity of CaM-KK isoforms to STO-609 is because of a single amino acid substitution (Val/Leu) in the ATP-binding pocket, we have generated an STO-609-resistant CaM-KK mutant, which might be useful for validating the pharmacological effects and specificity of STO-609 in vivo.
Related Links	http://www.jbc.org/content/278/13/10908.abstract
Ending Page	10913
Starting Page	10908
Page Count	6
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	13
Volume Number	278
DOI	10.1074/jbc.M213183200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2003-03-28
Access Restriction	Open
Subject Keyword	Ca2+/CaM-dependent protein kinase (CaM-K) Calmodulin (CaM) CAMP-dependent protein kinase (PKA) CAMP-response element binding protein (CREB) Hemagglutinin (HA) Glutathione S-transferase (GST) ENZYME CATALYSIS AND REGULATION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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