N-TRADD active site and uses thereof
AssigneeGenetics Institute, Inc.
InventorsDesiree H. H. Tsao, Jean-Baptiste Telliez, Thomas McDonagh, Lih-Ling Lin, Sang Hsu, Guang-Yi Xu, A. Karl Malakian
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Abstract
The present invention relates to the three dimensional solution structure of the N-terminal domain of TNFR-1 associated death domain protein (“N-TRADD”), as well as the identification and characterization of a C-TRAF2 binding active site of N-TRADD. Also provided for by the present invention are methods of utilizing the three dimensional structures for the design and selection of potent and selective inhibitors of TNF signaling pathways.
Claims47
A method for identifying an agent that interacts with N-terminal domain of TNFR- 1 associated death domain protein (N-TRADD), the method comprising:
- providing a solution comprising N-TRADD;
- displaying a three-dimensional model of an active site of N-TRADD, wherein the active site of N-TRADD comprises an N-terminal domain of TRADD that interacts with C-TRAF2 and wherein the three dimensional structure of the active site comprises the relative structural coordinates of amino acid residues Y16, L17, F18, V58, L59, K63, I64, H65, D68, Q70, I72, V73, Q74, L75, C78, L118, G121, A122, R124, L125, D149, E150, and L152 according to FIG. 2, ± a root mean square deviation from the conserved backbone atoms of the amino acids of the active site of not more than 1.5Å;
- using the three-dimensional structure of the active site of N-TRADD to design an agent that interacts with the active site of N-TRADD;
- and
- obtaining or synthesizing the agent.
A method for identifying an agent that interacts with N-terminal domain of TNFR-1 associated death domain protein (N-TRADD), the method comprising:
- displaying a three-dimensional model of an active site of N-TRADD, wherein the active site of N-TRADD comprises an N-terminal domain of TRADD that interacts with C-TRAF2 and wherein the three dimensional model of the active site of N-TRADD comprises the relative structural coordinates of amino acid residues Y16, L17, F18, V58, L59, K63, I64, H65, D68, Q70, I72, V73, Q74, L75, C78, L118, G121, A122, R124, L125, E150, and L152 according to FIG. 2, ± a root mean square deviation from the conserved backbone atoms of said amino acids of not more than 1.5Å;
- using the three-dimensional structure of the active site of N-TRADD to design an agent that interacts with the active site of N-TRADD;and
- obtaining or synthesizing the agent.
A method for identifying an agent that interacts with N-terminal domain of TNFR-1 associated death domain protein (N-TRADD), the method comprising:
- providing a solution comprising N-TRADD;
- using a three-dimensional structure of an active site of N-TRADD to design an agent that interacts with the active site of N-TRADD,
- wherein:
- the active site of N-TRADD comprises the relative structural coordinates of amino acid residues Y16, L17, F18, V58, L59, K63, I64, H65, D68, Q70, I72, V73, Q74, L75, C78, L118, G121, A122, R124, L125, E150, and L152 according to FIG. 2, ± a root mean square deviation from the conserved backbone atoms of said amino acids of not more than 1.5Å;
- and
- obtaining the agent.
A method for identifying an agent that interacts with N-terminal domain of TNFR-1 associated death domain protein (N-TRADD), the method comprising:
- providing a solution comprising N-TRADD;
- using a three-dimensional structure of an active site of N-TRADD to design an agent that interacts with the active site of N-TRADD,
- wherein:
- the active site of N-TRADD comprises the relative structural coordinates of amino acid residues Y16, L17, F18, V58, L59, K63, I64, H65, D68, Q70, I72, V73, Q74, L75, C78, L118, G121, A122, R124, L125, E150, and L152 according to FIG. 2, ± a root mean square deviation from the conserved backbone atoms of said amino acids of not more than 1.5 Å;
- obtaining the agent;
- and
- interacting the agent with the active site of N-TRADD to determine the effect the agent has on the activity of the active site of N-TRADD.
A method for identifying an agent that interacts with N-terminal domain of TNFR-1 associated death domain protein (N-TRADD), the method comprising:
- displaying a three-dimensional structure of an active site of N-TRADD, wherein the active site of N-TRADD comprises the relative structural coordinates of amino acid residues Y16, L17, F18, V58, L59, K63, I64, H65, D68, Q70, I72, V73, Q74, L75, C78, L118, G121, A122, R124, L125, E150, and L152 according to FIG. 2, ± a root mean square deviation from the conserved backbone atoms of said amino acids of not more than 1.5Å;
- evaluating the ability of the agent to associate with the three-dimensional structure of the active site of N-TRADD;
- and
- designing the agent and displaying graphical representing of the designed agent;
- wherein the agent is designed de novo or using known inhibitors of N-TRADD.
Dependencies are inferred from the claim text.