Inhibition of protein kinases by balanol: specificity within the serine/threonine protein kinase subfamily.
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.
Department of Pharmacology and Medicine, University of California at San Diego, La Jolla, California, USA.
J
J
Setyawan
K
K
Koide
T C
TC
Diller
M E
ME
Bunnage
S S
SS
Taylor
K C
KC
Nicolaou
L L
LL
Brunton
D000255:Adenosine Triphosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D020134:Catalytic Domain; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D001381:Azepines; D004791:Enzyme Inhibitors; D062385:Hydroxybenzoates; D007527:Isoenzymes; C015405:ophiocordin; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases