Ribosome structure and protein synthesis inhibitors

Abstract

The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.

1 . A protein synthesis inhibitor comprising:
 a first binding domain having a surface that mimics or duplicates a surface of a known first molecule that binds with a first contact site in a large ribosomal subunit; and   a second binding domain having a surface that mimics or duplicates a surface of a known second molecule that binds with a second contact site in the ribosomal subunit,   wherein the first domain is attached to the second domain so as to permit both the first domain and the second domain to bind with its respective contact site thereby to disrupt protein synthesis in a ribosomal subunit, and wherein the protein synthesis inhibitor has a molecular weight of less than about 1,500 and an IC 50  lower than about 50 μM.   
     
     
         2 . The inhibitor of  claim 1 , wherein the first molecule is a first antibiotic. 
     
     
         3 . The inhibitor of  claim 2 , wherein the first antibiotic binds at least a portion of a ribofunctional locus. 
     
     
         4 . The inhibitor of  claim 2 , wherein the first antibiotic is sparsomycin. 
     
     
         5 . The inhibitor of  claim 1 , wherein the second molecule is a second antibiotic. 
     
     
         6 . The inhibitor of  claim 5 , wherein the second antibiotic binds at least a portion of a ribofunctional locus. 
     
     
         7 . The inhibitor of  claim 5 , wherein the second antibiotic is anisomycin or chloramphenicol. 
     
     
         8 . The inhibitor of  claim 1 , wherein the inhibitor has a molecular weight in the range from about 250 to about 1500. 
     
     
         9 . The inhibitor of  claim 1 , wherein the inhibitor has an IC 50  in the range from about 0.001 μM to about 50 μM. 
     
     
         10 .- 12 . (canceled)