Alternate morpheeins of allosteric proteins as a target for the development of bioactive molecules

Abstract

A composition having an agent adapted to affect a multimeric protein by binding to a binding site of the multimeric protein and thereby affecting an equilibrium of units, wherein the multimeric protein has an assembly having a plurality of said units, wherein each of the units has a first complementary surface and a second complementary surface and wherein the first complementary surface of one unit is associated with the second complementary surface of another unit, provided that the assembly is at least one of different quaternary isoforms on a condition that in the multimeric protein (1) a structure of each of the units determines a structure of the different quaternary isoforms, (2) the units are in the equilibrium and (3) the structure of the different quaternary isoforms influences a function of the multimeric protein.

1 - 52 . (canceled) 
     
     
         53 . A method of inhibiting a multimeric protein comprising an equilibrium of assembly states, each assembly having a plurality of units, wherein each of said units comprises a first complementary surface and a second complementary surface and wherein the first complementary surface of one unit is associated with the second complementary surface of another unit, provided that the assembly is at least one of different quaternary isoforms on condition that:
 (i) one conformation of said units determines a first quaternary isoform but does not allow formation of other quaternary isoforms;   (ii) a different conformation of said units determines one of a different quaternary isoforms, but does not allow formation of the first quaternary isoform;   (iii) the different conformations of said units are in an equilibrium; and   (iv) the conformation of said different quaternary isoforms influences a function of said multimeric protein,   the method comprising;   applying to the multimeric protein a composition comprising an inhibitor adapted to inhibit formation of an active form of the multimeric protein;   associating the composition with a less active form of the multimeric protein;   inhibiting the less active form from assembling into the active form and thereby inhibiting the multimeric protein from forming the active form.   
     
     
         54 . The method of  claim 53 , wherein the multimeric protein is a member selected from the group consisting of kinases and phosphatases. 
     
     
         55 . The method of  claim 53 , wherein the unit is a member selected from the group consisting of a monomer, a dimer, a trimer, a tetramer, a hexamer, and an octamer. 
     
     
         56 . The method of  claim 53 , wherein the inhibitor is adapted to affect a function of said multimeric protein. 
     
     
         57 . The method of  claim 53 , wherein the inhibitor is bound to a quaternary isoform having a lesser activity. 
     
     
         58 . A method of modulating a physiological activity in a cell, a tissue or an organism, the method comprising:
 providing the cell, the tissue or the organism, wherein the cell, the tissue or the organism comprise a multimeric protein which comprises an equilibrium of assembly states, each assembly having a plurality of units, wherein each of said units comprises a first complementary surface and a second complementary surface and wherein the first complementary surface of one unit is associated with the second complementary surface of another unit, provided that the assembly is at least one of different quaternary isoforms on condition that:   (i) one conformation of said units determines a first quaternary isoform but does not allow formation of other quaternary isoforms;   (ii) a different conformation of said units determines one of a different quaternary isoforms, but does not allow formation of the first quaternary isoform;   (iii) the different conformations of said units are in an equilibrium; and   (iv) the conformation of said different quaternary isoforms influences a function of said multimeric protein;   providing an agent adapted to affect the equilibrium by binding to the binding site on the unit, thereby affecting the formation of a quaternary isoform, and   thereby modulating the physiological activity of the cell, tissue or organism.   
     
     
         59 . The method of  claim 58 , wherein the agent inactivates the enzymatic activity of the multimeric protein. 
     
     
         60 . The method of  claim 58 , wherein the agent is an inhibitor which inhibits formation of an active form of the multimeric protein. 
     
     
         61 . The method of  claim 58 , wherein the unit is a member selected from the group consisting of a monomer, a dimer, a trimer, a tetramer, a hexamer, and an octamer. 
     
     
         62 . The method of  claim 58 , wherein the agent is adapted to affect a function of said multimeric protein. 
     
     
         63 . The method of  claim 58 , wherein the agent is bound to a quaternary isoform having a lesser activity. 
     
     
         64 . The method of  claim 58 , wherein said multimeric protein is a member selected from the group consisting of porphobilinogen synthase, a Class Ia ribonucleotide reductase,  Pseudomonas aeruginosa  GDP-Mannose dehydrogenase,  Bacillus subtilis  HPr, kinase/phosphatase, mammalian CoA transferase, purine nucleoside phosphorylase, and peroxiredoxins.