Protein synthesis modulators

Abstract

The invention provides a high resolution three-dimensional structure of a deacylated transfer RNA protein synthesis modulator in association with a large ribosomal subunit. The protein synthesis modulator binds at least a portion of the E-site of a large ribosomal subunit. The invention provides methods for designing and/or identifying analogs of candidate molecules, for example, analogs or derivatives of the protein synthesis modulator, that bind and/or modulate the protein biosynthetic activity of the ribosome.

1 .- 18 . (canceled) 
     
     
         19 . A method of identifying a candidate molecule, the method comprising the steps of:
 (a) providing a molecular model of at least a portion of an RNA microhelix molecule bound to a RNA microhelix binding site of a large subunit of a ribosome;   (b) using the molecular model to identify a candidate molecule capable of binding to the RNA microhelix binding site; and   (c) producing the candidate molecule identified in step (b).   
     
     
         20 . The method of  claim 19 , wherein the candidate molecule is capable of interacting stereochemically with the binding site. 
     
     
         21 . The method of  claim 19 , wherein the candidate molecule is capable of binding specifically to the binding site. 
     
     
         22 . The method of  claim 19  comprising the additional step of determining whether the candidate molecule modulates ribosomal activity. 
     
     
         23 . The method of  claim 22  comprising the additional step of modifying the candidate molecule. 
     
     
         24 . The method of  claim 23  comprising the additional step of producing the modified candidate molecule. 
     
     
         25 . The method of  claim 24  comprising the additional step of determining whether the candidate molecule modulates ribosomal activity. 
     
     
         26 . The method of  claim 25  comprising the additional step of producing the candidate molecule. 
     
     
         27 . The method of  claim 19 , wherein the molecular model is defined by at least a portion of the atomic co-ordinates recorded on Replacement Disk No. 1 under file name microhelix.txt or microhelixa.txt. 
     
     
         28 . An antibiotic produced by the method of claim  1 . 
     
     
         29 . (canceled) 
     
     
         30 . A method of identifying a candidate molecule, the method comprising the steps of:
 (a) providing a molecular model of at least a portion of an RNA microhelix when the RNA microhelix is interacting with an RNA microhelix binding site of a large subunit of a ribosome; and   (b) using the model to identify a candidate molecule capable of interacting with the binding site.   
     
     
         31 . The method of  claim 30 , wherein the candidate molecule is capable of interacting stereochemically with the binding site. 
     
     
         32 . The method of  claim 30 , wherein the candidate molecule is capable of binding the binding site. 
     
     
         33 . The method of  claim 30  comprising the additional step of producing the candidate molecule identified in step (b). 
     
     
         34 . The method of  claim 33  comprising the additional step of determining whether the candidate molecule modulates ribosomal activity. 
     
     
         35 . The method of  claim 34  comprising the additional step of modifying the candidate molecule. 
     
     
         36 . The method of  claim 35  comprising the additional step of producing the modified candidate molecule. 
     
     
         37 . The method of  claim 36  comprising the additional step of determining whether the modified candidate molecule modulates ribosomal activity. 
     
     
         38 . The method of  claim 36  comprising the additional step of producing the modified candidate molecule. 
     
     
         39 . The method of  claim 30 , wherein the candidate molecule is an antibiotic. 
     
     
         40 . The method of  claim 36 , wherein the modified candidate molecule is an antibiotic. 
     
     
         41 . The method of  claim 30 , wherein the molecular model is defined by at least a portion of the atomic co-ordinates recorded on Replacement Disk No. 1 under file name microhelix.txt. 
     
     
         42 . The method of  claim 30 , wherein the molecular model is defined by at least a portion of the atomic co-ordinates recorded on Replacement Disk No. 1 under file name microhelixa.txt. 
     
     
         43 . The method of  claim 30 , wherein the molecular model is defined by at least a portion of the atomic co-ordinates recorded on Replacement Disk No. 1 under file name 1JJ2.txt. 
     
     
         44 . The method of  claim 30 , wherein the molecular model is in an electronic form. 
     
     
         45 .- 89 . (canceled)