Three-dimensional structures of tall-1 and its cognate receptors and modified proteins and methods related thereto

Abstract

Disclosed are TALL-1 and TALL-1 receptor protein homologues (agonists and antagonists) designed based on the three-dimensional structure of sTALL-1, eBCMA and eBAFF-R; agonist homologues of APRIL; methods of using wild-type APRIL to inhibit the activity of TALL-1; compositions comprising such homologues, nucleic acid molecules encoding such homologues, and therapeutic methods of using such compounds and compositions. Also disclosed are crystalline complexes of sTALL-1 and sTALL-1 in complex with either BCMA or BAFF-R; models of three-dimensional structures of such crystalline complexes and related structures, methods of drug design using any portion of such structures; methods of design and/or identification of regulatory peptides derived from the such structures; compounds identified by drug design using such structures; and the use of such compounds in therapeutic compositions and methods.

1 .- 61 . (canceled) 
     
     
         62 . A BCMA antagonist, wherein said receptor antagonist comprises an amino acid sequence that differs from SEQ ID NO:6 by a modification in at least one amino acid residue selected from the group consisting of: Tyr13, Asp15, Leu17, Leu18, His19, Ile22, Leu26, Arg27, and Pro34;
 wherein said BCMA antagonist has an increased binding affinity for TALL-1 as compared to wild-type BCMA.   
     
     
         63 . The BCMA antagonist of  claim 62 , wherein said amino acid residue is selected from the group consisting of Leu17 and Leu18. 
     
     
         64 . The BCMA antagonist of  claim 62 , wherein said amino acid residue is selected from the group consisting of Ile22 and Leu26. 
     
     
         65 . The BCMA antagonist of  claim 62 , wherein said amino acid residue is selected from the group consisting of Asp15, Arg27 and Tyr13. 
     
     
         66 . The BCMA antagonist of  claim 62 , wherein said amino acid residue is His19. 
     
     
         67 . The BCMA antagonist of  claim 62 , wherein said amino acid residue is selected from the group consisting of Tyr13, Leu17, Leu18 and Ile22. 
     
     
         68 . The BCMA antagonist of  claim 67 , wherein said amino acid residue is substituted with an amino acid residue selected from the group consisting of: Ile, Met, Phe or Tyr. 
     
     
         69 . The BCMA antagonist of  claim 62 , wherein said BCMA antagonist is a soluble protein. 
     
     
         70 . A BAFF-R antagonist, wherein said receptor antagonist comprises an amino acid sequence that differs from SEQ ID NO:8 by a modification in at least one amino acid residue selected from the group consisting of: Asp26, Leu28, Val29, Arg30, Val33, Leu37, Leu38, and Arg42, and Pro45;
 wherein said BAFF-R antagonist has an increased binding affinity for TALL-1 as compared to wild-type BAFF-R.   
     
     
         71 . The BAFF-R antagonist of  claim 70 , wherein said amino acid residue is selected from the group consisting of Leu28 and Val29. 
     
     
         72 . The BAFF-R antagonist of  claim 70 , wherein said amino acid residue is selected from the group consisting of Val33, Leu37, Leu38 and Pro45. 
     
     
         73 . The BAFF-R antagonist of  claim 70 , wherein said amino acid residue is selected from the group consisting of Asp26 and Arg 42. 
     
     
         74 . The BAFF-R antagonist of  claim 70 , wherein said amino acid residue is selected from the group consisting of Arg30. 
     
     
         75 . The BAFF-R antagonist of  claim 70 , wherein said amino acid residue is selected from the group consisting of Leu28, Val29 and Val33. 
     
     
         76 . The BAFF-R antagonist of  claim 75 , wherein said amino acid residue is substituted with an amino acid residue selected from the group consisting of: Ile, Met, Phe or Tyr. 
     
     
         77 . The BAFF-R antagonist of  claim 70 , wherein said BAFF-R antagonist is a soluble protein. 
     
     
         78 . A method to inhibit TALL-1 receptor biological activity in a mammal, comprising administering to said mammal the antagonist of  claim 62 . 
     
     
         79 . The method of  claim 78 , wherein said antagonist is a competitive inhibitor of a wild-type TALL-1 receptor for binding to TALL-1. 
     
     
         80 . A method to inhibit the biological activity of TALL-1, comprising administering to a cell that expresses TALL-1 a recombinant nucleic acid molecule comprising a nucleic acid sequence encoding APRIL, or a biologically active fragment thereof. 
     
     
         81 . An isolated BAFF-R antagonist, wherein said BAFF-R antagonist consists essentially of the amino acid sequence represented by SEQ ID NO:9, or homologues thereof with substantially the same biological activity. 
     
     
         82 .- 99 . (canceled) 
     
     
         100 . A method to inhibit TALL-1 receptor biological activity in a mammal, comprising administering to said mammal the antagonist of  claim 70 . 
     
     
         101 . The method of  claim 100 , wherein said antagonist is a competitive inhibitor of a wild-type TALL-1 receptor for binding to TALL-1.