Inhibition of Protein Kinases by Balanol: Specificity within the Serine/Threonine Protein Kinase Subfamily
- Juliana Setyawan1,
- Kazunori Koide2,
- Thomas C. Diller2,
- Mark E. Bunnage2,3,
- Susan S. Taylor2,
- K. C. Nicolaou2,3 and
- Laurence L. Brunton1
- Departments of 1Pharmacology and Medicine (J.S., L.L.B.) and2Chemistry and Biochemistry (K.K., T.C.D., M.E.B., S.S.T., K.C.N.), University of California at San Diego, La Jolla, California; and3Department of Chemistry, The Scripps Research Institute, La Jolla, California (M.E.B., K.C.N.)
Abstract
Balanol is a potent inhibitor of cyclic AMP-dependent protein kinase and protein kinase C, acting competitively with ATP with an affinity 3000 times that of ATP. We tested the capacity of balanol to inhibit representative serine- and threonine-specific protein kinases from the protein kinase subfamily that shares a common conserved catalytic core with cyclic AMP-dependent protein kinase. Balanol’s pattern of interactions indicates considerable diversity of the ATP/balanol-binding sites of protein kinases within familial groups and even among isoforms of the same kinase. We propose that balanol is a protean structure that may be modified to produce selective, high-affinity inhibitors and probes of the ATP-binding sites of serine/threonine protein kinases.
Footnotes
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Send reprint requests to: Laurence L. Brunton, Ph.D., Department of Pharmacology 0636, University of California San Diego, School of Medicine, La Jolla, CA 92093. E-mail:lbrunton{at}ucsd.edu
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This work was supported by National Institutes of Health Grants HL41307 and GM19301, a Lucille P. Markey fellowship, and an NSF predoctoral fellowship (to T.C.D.).
- Abbreviations:
- PKA
- cyclic AMP-dependent protein kinase
- PKC
- protein kinase C
- cGMP
- cyclic GMP
- PKG
- cyclic GMP-dependent protein kinase
- PhK
- phosphorylase kinase
- smMLCK
- smooth muscle myosin light chain kinase
- CaMKII
- Ca2+-calmodulin-activated kinase II
- MAPK
- mitogen-activated protein kinase
- p34cdc2
- cyclin-dependent kinase
- CKII
- casein kinase II
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- Received February 11, 1999.
- Accepted April 8, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
