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 mulfimeric protein and thereby affecting an equilibrium of units, wherein the mulfimeric 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 . A composition comprising an agent adapted to affect a multimeric protein by binding to a binding site of said multimeric protein and thereby affecting an equilibrium of units, wherein said multimeric protein comprises an assembly having a plurality of said 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 a condition that in said multimeric protein (1) a structure of each of said units determines a structure of said different quaternary isoforms, (2) said units are in the equilibrium and (3) the structure of said different quaternary isoforms influences a function of the multimeric protein.  
     
     
         2 . The composition of  claim 1 , wherein affecting said multimeric protein comprises affecting a formation of a quaternary isoform.  
     
     
         3 . The composition of  claim 1 , wherein affecting said multimeric protein comprises affecting the function of said multimeric protein.  
     
     
         4 . The composition of  claim 3 , wherein the function of said multimeric protein is an activity and wherein affecting is at least one of inhibiting or activating.  
     
     
         5 . The composition of  claim 4 , wherein the agent is bound to at least one of a quaternary isoform having a lesser activity or a quaternary isoform having a greater activity.  
     
     
         6 . The composition of  claim 1 , wherein each of said units is a member selected from the group consisting of a monomer, a dimer, a trimer, a tetramer, a hexamer, and an octamer.  
     
     
         7 . The composition of  claim 1 , 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.  
     
     
         8 . The composition of  claim 7 , wherein said multimeric protein is porphobilinogen synthase comprising eight porphobilinogen synthase monomers.  
     
     
         9 . The composition of  claim 8 , wherein the agent is an inhibitor bound to the quaternary isoform having the lesser activity and wherein the quaternary isoform contains less than eight porphobilinogen synthase monomers.  
     
     
         10 . The composition of  claim 7 , wherein said multimeric protein is the Class Ia ribonucleotide reductase and the agent inhibits the Class Ia ribonucleotide reductase through selective binding to the binding site that is unique to the quatemary isoform having the lesser activity.  
     
     
         11 . A composition comprising an inhibitor adapted to inhibit formation of an active form of a multimeric porphobilinogen synthase having a first number of monomers by binding to a less active form of the multimeric porphobilinogen synthase having a second number of monomers, wherein the first number of monomers is higher than the second number of monomers.  
     
     
         12 . The composition of  claim 1   1 , wherein the multimeric porphobilinogen synthase is derived from bacteria, archaea, or eucarya, provided that the octameric porphobilinogen synthase contains an allosteric magnesium binding site.  
     
     
         13 . The composition of  claim 12 , wherein the multimeric porphobilinogen synthase contains a catalytic zinc binding site.  
     
     
         14 . The composition of  claim 1   1 , wherein the multimeric porphobilinogen synthase does not contain the allosteric magnesium binding site and the catalytic zinc binding site.  
     
     
         15 . The composition of  claim 11 , wherein said less active form is a hexamer.  
     
     
         16 . The composition of  claim 1   1 , wherein said less active form is a dimer.  
     
     
         17 . The composition of  claim 11 , wherein the inhibitor replaces a metal ion and thereby binds at a metal ion binding site.  
     
     
         18 . The composition of  claim 17 , wherein the metal ion is zinc and/or magnesium.  
     
     
         19 . The composition of  claim 1   1 , wherein the inhibitor binds at an active site.  
     
     
         20 . The composition of  claim 11 , wherein the inhibitor is not a metal cation.  
     
     
         21 . The composition of  claim 11 , wherein the inhibitor is adapted to inhibit formation of the active form of the multimeric porphobilinogen synthase, said active form is an octomeric porphobilinogen synthase by binding to a hug-disabling domain of the less active form of the multimeric porphobilinogen synthase containing less than eight monomers.  
     
     
         22 . The composition of  claim 11 , wherein the inhibitor is adapted to inhibit formation of the active form of the multimeric porphobilinogen synthase by binding at a site other than an active site and/or metal ion binding site.  
     
     
         23 . The composition of  claim 11 , wherein the inhibitor is adapted to inhibit formation of the active form of the multimeric porphobilinogen synthase by a mechanism other than removing a metal ion.  
     
     
         24 . The composition of  claim 11 , further comprising a delivery medium, said delivery medium is a member selected from the group consisting of a pharmaceutically-acceptable medium, an orally-acceptable carrier, an antibacterial medium, and a herbicidally-effective medium.  
     
     
         25 . The composition of  claim 24 , wherein the composition is effective to inhibit or prevent formation of the active form of the multimeric porphobilinogen synthase and thereby inhibiting or preventing development or growth of bacteria, archaea, and/or eucarya, provided that the active form of the multimeric porphobilinogen synthase contains an allosteric magnesium binding site.  
     
     
         26 . The composition of  claim 25 , effective to cure or prevent a disease caused by contacting bacteria, archaea, and/or eucarya.  
     
     
         27 . The composition of  claim 25 , wherein the composition is at least one of a drug, a toothpaste, a soap, a disinfectant, an anti-biofilm composition, and a herbicide.  
     
     
         28 . The composition of  claim 24 , wherein the composition is effective to inhibit or prevent formation of the active form of the multimeric porphobilinogen synthase and thereby inhibiting or preventing development or growth of bacteria, archaea, and/or eucarya, provided that the active form of the multimeric porphobilinogen synthase does not contain the allosteric magnesium binding site and the catalytic zinc.  
     
     
         29 . The composition of  claim 28 , effective to cure or prevent a disease or caused by contacting bacteria, archaea, and/or eucarya.  
     
     
         30 . The composition of  claim 28 , wherein the composition is at least one of a drug, a toothpaste, a soap, and a disinfectant.  
     
     
         31 . A herbicide resistant plant adapted to be transgenic for a multimeric porphobilinogen synthase that substantially exist in a multimeric form of a hugging dimer.  
     
     
         32 . The herbicide resistant plant of  claim 31 , wherein the multimeric porphobilinogen synthase is derived from a human.  
     
     
         33 . The herbicide resistant plant of  claim 31 , wherein the multimeric porphobilinogen synthase contains no allosteric magnesium binding site.  
     
     
         34 . A composition comprising an inhibitor adapted to bind to a multimeric porphobilinogen synthase that does not require zinc for catalytic function.  
     
     
         35 . A method of affecting a multimeric protein, the method comprising: 
 providing said multimeric protein comprising an 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 a condition that (1) a structure of said units determines a structure of said different quatemary isoforms, (2) said units are in an equilibrium and (3) the structure of said different quaternary isoforms influences a function of said multimeric protein;    providing the composition of  claim 1  comprising the agent, wherein the agent is adapted to affect the equilibrium by binding to a binding site on the assembly; and    contacting the assembly with the agent, wherein the agent affects the equilibrium by binding to the binding site and thereby affecting said multimeric protein.    
     
     
         36 . The method of  claim 35 , wherein affecting said multimeric protein comprises affecting a formation of a quaternary isoform.  
     
     
         37 . The method of  claim 35 , wherein affecting said mulfimeric protein comprises affecting a function of said multimeric protein.  
     
     
         38 . The method of  claim 35 , wherein the unit is a member selected from the group consisting of a momomer, a dimer, a trimer, a tetramer, a hexamer, and an octamer.  
     
     
         39 . The method of  claim 35 , wherein the agent is adapted to affect a function of said multimeric protein.  
     
     
         40 . The method of  claim 39 , wherein the function of said multimeric protein is an activity and wherein affecting is at least one of inhibiting or activating.  
     
     
         41 . The method of  claim 40 , wherein the agent is bound to at least one of a quaternary isoform having a lesser activity or a quatemary isoform having a greater activity.  
     
     
         42 . The method of  claim 41 , wherein the agent is bound to the quaternary isoform having a greater activity.  
     
     
         43 . The method of  claim 35 , 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.  
     
     
         44 . The method of  claim 43 , wherein said multimeric protein is porphobilinogen synthase comprising eight porphobilinogen synthase monomers.  
     
     
         45 . The method of  claim 43 , wherein said multimeric protein is the Class Ia ribonucleotide reductase and the agent inhibits the Class Ia ribonucleotide reductase through selective binding to the binding site that is unique to the quaternary isoform having the lesser activity.  
     
     
         46 . 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 comprising an assembly having a plurality of units, wherein each of the 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 a condition that (1) a structure of said units determines a structure of said different quaternary isoforms, (2) said units are in an equilibrium and (3) the structure of said different quaternary isoforms influences a function of the multimeric protein; and    providing the composition of  claim 1  comprising the agent to the cell, the tissue or the organism, wherein the agent is adapted to affect the equilibrium by binding to the binding site on the unit and thereby affecting the formation of a quaternary isoform and thereby modulating the physiological activity.    
     
     
         47 . A method of inhibiting a multimeric porphobilinogen synthase from forming an active form, the method comprising: 
 applying the composition of  claim 11  to the multimeric porphobilinogen synthase;    associating the composition with the less active form;    inhibiting the less active form from assembling into the active form and thereby inhibiting the multimeric porphobilinogen synthase from forming the active form.    
     
     
         48 . A method for manipulating growth or development of a plant comprising applying the composition of  claim 27  to the plant, wherein the plant is herbicide resistant and is adapted to be transgenic for a multimeric porphobilinogen synthase that substantially exist in a multimeric form of a hugging dimer.  
     
     
         49 . The method of  claim 48 , wherein the multimeric porphobilinogen synthase contains no allosteric magnesium binding site.  
     
     
         50 . A method of making an antibacterial surface, the method comprising: 
 providing the composition of  claim 27;     providing a surface-forming matrix;    combining the composition with the surface-forming matrix and thereby making the antibacterial surface.    
     
     
         51 . The method of  claim 50 , wherein the antibacterial surface is adapted to prevent or inhibit a formation of a biofilm.  
     
     
         52 . The composition of  claim 11 , wherein the inhibitor is rosmarinic acid or a derivative thereof.