Characterization of the Digitalis Receptor and Digitalis Mimics

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; R o o t E n t r y F ! Lr C o m p O b j b W o r d D o c u m e n t O b j e c t P o o l mÕGr mÕGr 2 3 4 5 6 7 8 9 : ; F Microsoft Word 6.0 Document MSWordDoc Word.Document.6 ; E +E @t E u ~ u E +E = u t F E U F V t E U v n E U - F V v RP X # t0 E + Hu& 9E u 9U u W u u O$ ^_ v ~ F V ~ ~ t e tq t& ~ '@;E ~# } u E @;E | } } 9422022 Ball The long term goal of this research is to gain an understanding of the structure and functioning of the cation transporter, Na,K ATPase, with a particular interest in elucidating the molecular mechanisms of digitalis (cardiac glycosides) binding and inhibition of this enzyme. The P.I. proposes to use a relatively new and perhaps unconventional approach to identify and characterize short peptide sequences which may mimic the glycosides, which are nonpeptidic steroid based plant products. The peptides will be selected from bacteriophage contained "random peptide libraries". The diversity of these selected peptides will help us understand how the glycosides bind and how their actions may be modified. In addition, since the enzyme's digitalis binding site has not been determined, the P.I. will also attempt to use anti idiotypic antibodies (raised to anti digoxin antibodies) to identify the binding site. The random peptide libraries will also be used to determine whether it is possible to generate a model digitalis binding site(s) This work has the potential of enabling us to identify serum proteins which serve as natural regulatory proteins. %%% The Na,K-ATPase is a membrane bound enzyme that uses energy in the form of ATP to transport sodium and potassium ions across the cell membrane. It is this maintenance of the levels of these two important cations that is the driving force for the active transport of small molecules such as amino acids, glucose, phosphate and calcium, as well as providing the basis for the action potential in nerve and muscle cells. The Na, K-ATPase is also the receptor for digitalis, a plant glycoside, which inhibits the enzyme in a highly specific manner. This project uses a new immunological approach to learn more about the mechanism of digitalis binding, and should in addition help in identifying the long sought after natural, or endogenous, molecule that acts to regulate the enzyme. ....()()))()() ; Oh +' 0 $ H l D h R:\WWUSER\TEMPLATE\NORMAL.DOT marcia steinberg marcia steinberg @ ? n @ @ (r S u m m a r y I n f o r m a t i o n ( 1 @ NZ Microsoft Word 6.0 2 e 3 e " " " " " " " L L L L L d n L C x | | | | | | | _ P T 4 " | | | | | | " " | x | | | | " | " | 6 " " " " | | 3 | 9422022 Ball The long term goal of this research is to gain an understanding of the structure and functioning of the cation transporter, Na,K ATPase, with a particular interest in elucidating the molecular mechanisms of digitalis (cardiac glycosides) binding and inhibition of this enzyme. The P.I. proposes to use a relatively new and perhaps unconventional approach to identify and characterize short peptide sequences which may mimic the glycosides, which are nonpeptidic steroid based plant products. The peptides will be selected from bacteriophage contained "random p