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Minimal Structural Requirements for Diglyceride-Site Directed Activators of Protein Kinase C

✍ Scribed by Michal Marom; Craig A. Parish; José-Luis Giner; Robert R. Rando

Publisher
Elsevier Science
Year
1997
Tongue
French
Weight
950 KB
Volume
53
Category
Article
ISSN
0040-4020

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✦ Synopsis

The importantregulatoryenzymeproteinkinase C is physiologicallyactivatedby the interactionof (S)-diglycerideswith its regulatorydomain. This interactioncan be mimickedby the structurallydiversetumorpromoters,whichshare,alongwith the diglycerides,the commonstructural featureof three hydrophilicatomsat the verticesofa trianglewith sides of approximately6 A. It is shown in this article that moleculeswith the sametriangukuarrangementof hydrophilic atomsbut with shorter sidescan also activatePKC. S-Fa.mesylthiotriazole (FTT) is a heterocyclicmoleculepreviouslyshownto specificallyactivatePKC. In the workreportedhere,structure-activitystudiesin the FIT seriesreveal that three hydrophilicatomsare requiredfor activation,and that the minimalactivationunit is close to an equilateraltrianglewith sidesof between2.4 -2.7 ,&. This demonstratesthat there is an unanticipated flexibilityat the PKC regulatorysite. The intermolecularactivationmodelbasedon structuralanalysisof the tumorpromotersmay representthe maximumdistancesallowedbetweenthe hydrophilicatomsof a PKC activator. 01997

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