Modulating nuclear receptor coactivator binding

Abstract

The present invention comprises cocrystal of a nuclear receptor comprising a molecule bound to the coactivator binding site of said nuclear receptor. The present invention further comprises a machine-readable data storage medium encoded with machine readable data corresponding to the structure coordinates of amino acids of a nuclear receptor coactivator binding site which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecular complex of a compound bound to a nuclear receptor coactivator binding site.

1 . A cocrystal of a nuclear receptor comprising a molecule bound to the coactivator binding site of said nuclear receptor.  
     
     
         2 . The cocrystal of  claim 1 , wherein said nuclear receptor is a thyroid receptor.  
     
     
         3 . The cocrystal of  claim 2 , wherein said thyroid receptor is human.  
     
     
         4 . The cocrystal of  claim 3 , wherein said molecule is peptide.  
     
     
         5 . The cocrystal of  claim 4 , wherein said peptide comprises a NR-box amino acid sequence or derivative thereof.  
     
     
         6 . The cocrystal of  claim 4  wherein the peptide comprises a nuclear receptor box sequence.  
     
     
         7 . The cocrystal of  claim 4  wherein the peptide consists of a portion of GRIP1 comprising a nuclear receptor box 2 sequence, wherein the portion is given by SEQ ID NO: 6.  
     
     
         8 . The cocrystal of  claim 7  wherein the peptide consists of a sequence selected from the group consisting of: residues 11-23 of SEQ ID NO: 6, residues 12-24 of SEQ ID NO: 6, residues 14-24 of SEQ ID NO: 6, residues 14-22 of SEQ ID NO: 6, and residues 7-23 of SEQ ID NO: 6.  
     
     
         9 . The cocrystal of  claim 6  wherein the nuclear receptor box sequence is ILHRLL.  
     
     
         10 . The cocrystal of  claim 6  wherein the peptide consists of a portion of GRIP1 comprising a nuclear receptor box 3 sequence, wherein the portion is given by SEQ ID NO: 7.  
     
     
         11 . The cocrystal of  claim 3  wherein the peptide comprises a sequence selected from the group consisting of: residues 9-21 of SEQ ID NO: 7, residues 8-24 of SEQ ID NO: 7, residues 5-24 of SEQ ID NO: 7.  
     
     
         12 . The cocrystal of  claim 6  wherein the nuclear receptor box sequence is LLRYLL.  
     
     
         13 . The cocrystal of  claim 4  wherein the peptide has sequence SEQ ID NO: 31.  
     
     
         14 . A machine-readable data storage medium, comprising a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecular complex of a compound bound to a nuclear receptor coactivator binding site comprising structure coordinates of amino acids corresponding to human thyroid receptor amino acids selected from the group consisting of helix 3 residues Ile280, Thr281, Val283, Val284, Ala287, and Lys288, helix 4 residue Phe293, helix 5 residues Gln301, Ile302, Leu305, Lys306, helix 6 residue Cys309, and helix 12 residues Pro453, Leu454, Glu457, Val458 and Phe459, or a homologue of said molecular complex, wherein said homologue comprises a coactivator binding site that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å.  
     
     
         15 . The machine readable storage medium of  claim 14 , wherein said nuclear receptor is a thyroid receptor.  
     
     
         16 . The machine readable storage medium of  claim 15 , wherein said thyroid receptor is human.  
     
     
         17 . The machine readable storage medium of  claim 16 , wherein said molecule is peptide.  
     
     
         18 . The machine readable storage medium of  claim 17 , wherein said peptide comprises a NR-box amino acid sequence, or derivative thereof.  
     
     
         19 . The machine-readable data storage medium according to  claim 14 , wherein said molecular complex is defined by the set of structure coordinates depicted in Appendix 1, or a homologue of said molecular complex, said homologue having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å.  
     
     
         20 . A machine-readable data storage medium comprising a data storage material encoded with a first set of machine readable data which, when combined with a second set of machine readable data, using a machine programmed with instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data, wherein: said first set of data comprises a Fourier transform of at least a portion of the structural coordinates selected from the group consisting of coordinates depicted in Appendix 1; and said second set of data comprises an X-ray diffraction pattern of a molecule or molecular complex.