IP Library › Granted Patent US 7,379,820
Granted Patent B2
US 7,379,820 · App. 10/359,439 · Granted May 27, 2008

Solution structure of RIP DD and uses thereof

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Quick Facts
Patent No.
US 7,379,820
App. No.
10/359,439
Granted
May 27, 2008
Kind
B2
Abstract

The present invention relates to the three dimensional solution structure of receptor interacting protein dead domain (RIP DD), as well as the identification and characterization of various binding active sites of RIP DD. Also provided for by the present invention are methods of utilizing the three dimensional structure for the design and selection of potent and selective inhibitors of TNF signaling pathways.

Claims (28)

1. A method for identifying an agent that inhibits Receptor Interacting Protein death domain (RIP DD), comprising:

providing a solution comprising RIP DD;

determining the three dimensional structure of RIP DD in the solution;

identifying an active site of RIP DD from the three dimensional structure of RIP DD, wherein the three dimensional structure comprises the relative structural coordinates of RIP DD as represented in FIGS. 6 to 6 A- 38 , ± a root mean square deviation from the backbone atoms of RIP DD of not more than 1.5 Å; and

performing computer fitting analysis to identify an agent which inhibits said active site.

2. The method of claim 1 , wherein the ± a root mean square deviation from the backbone atoms of RIP DD is not more than 1.0 Å.

3. The method of claim 1 , wherein the ± a root mean square deviation from the backbone atoms of RIP DD is not more than 0.5 Å.

4. The method of claim 1 , further comprising contacting the identified agent with a RIP DD and determining the effect the agent has on RIP DD activity.

5. The method of claim 4 , wherein the agent inhibits RIP DD activity.

6. The method of claim 1 , further comprising contacting the identified agent with a RIP DD in the presence of a RIP DD binding molecule, and determining the effect the agent has on binding of the RIP DD to the RIP DD binding molecule.

7. The method of claim 1 , wherein the structure is determined using NMR spectroscopy.

8. The method of claim 1 , wherein RIP DD comprises amino acid residues K596-L605 (α1 helix), amino acid residues Q609-D622 (α2 helix), amino acid residues V628-E639 (α3 helix), amino acid residues T645-Q655 (α4 helix) of RIP DD, and amino acid residues I659-L665 (α3 helix), of FIG. 1 (SEQ ID NO:1), or conservative substitutions thereof.

9. The method of claim 1 , wherein RIP DD comprises amino acid residues 574-671 of FIG. 1 (SEQ ID NO:1), or conservative substitutions thereof.

10. The method of claim 1 , further comprising storing the three-dimensional structure of the active site of RIP DD in a machine readable storage medium.

11. The method of claim 1 , further comprising displaying the three dimensional structure of RIP DD.

12. A method for identifying an agent that inhibits Receptor Interacting Protein death domain (RIP DD), comprising:

providing a solution comprising RIP DD;

determining the three dimensional structure of RIP DD in the solution;

identifying an active site of RIP DD from the three dimensional structure of RIP DD, wherein the active site comprises the relative structural coordinates of amino acid residues D6 13, H617, D618, R621, K625, E626 and K627 according to FIGS. 6 to 6 A- 38 , ± a root mean square deviation from the backbone atoms of RIP DD of not more than 1.5 Å.

13. The method of claim 12 , wherein the ± a root mean square deviation from the backbone atoms of RIP DD is not more than 1.0 Å.

14. The method of claim 12 , wherein the ± a root mean square deviation from the backbone atoms of RIP DD is not more than 0.5 Å.

15. The method of claim 12 , wherein the active site further comprises the relative structural coordinates of amino acid residues K599 and R603 according to FIGS. 6 to 6 A- 38 , ± a root mean square deviation from the backbone atoms of RIP DD is not more than 1.5 Å.

16. The method of claim 15 , wherein the ± a root mean square deviation from the backbone atoms of RIP DD is not more than 1.0 Å.

17. The method of claim 15 , wherein the ± a root mean square deviation from the backbone atoms of RIP DD is not more than 0.5 Å.

18. The method of claim 12 , wherein RIP DD comprises amino acid residues K596-L605 (α1 helix), amino acid residues Q609-D622 (α2 helix), amino acid residues V628-E639 (α3 helix), amino acid residues T645-Q655 (α4 helix) of RIP DD, and amino acid residues I659-L665 (α3 helix), of FIG. 1 (SEQ ID NO:1), or conservative substitutions thereof.

19. The method of claim 12 , wherein RIP DD comprises amino acid residues 574-671 of FIG. 1 (SEQ ID NO:1), or conservative substitutions thereof.

20. The method of claim 12 , further comprising storing the three-dimensional structure of the active site of RIP DD in a machine readable storage medium.

21. The method of claim 12 , further comprising displaying the three dimensional structure of RIP DD.