Crystal structure of bace and uses thereof
AssigneeAmerican Home Products Corporation
InventorsRajiv Chopra, Kristine Svenson, Bethany Annis, Tatos N. Akopian, Jonathan Bard, Mark Lloyd Stahl, William S. Somers
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Abstract
This invention is directed to the three dimensional crystal structure of Beta-site APP Cleaving Enzyme (BACE), and to the use of this structure in rational drug design methods to identify agents that may interact with active sites of BACE. Such agents may represent new therapeutics in the treatment and/or prevention of Alzheimer's Disease.
Claims30
A crystallized complex of Beta-site APP Cleaving Enzyme (BACE) and SER—GLU—VAL—ASN—Sta—VAL—ALA—GLU—PHE.
An active site of an APP binding protein or peptide comprising the relative structural coordinates according to FIG. 1 of residues SER71, GLY72, LEU91, ASP93, GLY95, SER96, VAL130, PRO131, TYR132, THR133, GLN134, ILE171, ILE179, ILE187, ALA188, ARG189, PRO190, TRP258, TYR259, ASP284, LYS285, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and ARG368, ±a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å.
An active site of an APP binding protein or peptide comprising the relative structural coordinates according to FIG. 1 of residues LYS70, SER71, GLY72, GLN73, GLY74, TYR75, LEU91, VAL92, ASP93, THR94, GLY95, SER96, SER97, ASN98, TYR129, VAL130, PRO131, TYR132, THR133, GLN134, GLY135, LYS136, TRP137, LYS168, PHE169, PHE170, ILE171, ASN172, SER174, TRP176, GLY178, ILE179, LEU180, GLY181, ALA183, TYR184, ALA185, GLU186, ILE187, ALA188, ARG189, PRO190, ASP191, ASP192, ARG256, TRP258, TYR259, TYR283, ASP284, LYS285, SER286, ILE287, VAL288, ASP289, SER290, GLY291, THR292, THR293, ASN294, LEU295, ARG296, GLY325, GLU326, ARG368, VAL370, LYS382, PHE383, ALA384, ILE385, SER386, GLN387, SER388, SER389, THR390, GLY391, THR392, VAL393, GLY395, ALA396 and ILE447, ±a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å.
A method for identifying an agent that interacts with an active site of Beta-site APP Cleaving Enzyme (BACE), comprising the steps of:
- (a) determining an active site of BACE from a three dimensional model of BACE using the relative structural coordinates of FIG. 1, ±a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å;
- and
- (b) performing computer fitting analysis to identify an agent which interacts with said active site.
A method for identifying an agent that interacts with an active site of an APP binding protein or peptide, comprising the steps of:
- (a) generating a three dimensional model of an active site of an APP binding protein or peptide using the relative structural coordinates according to FIG. 1 of residues SER71, GLY72, LEU91, ASP93, GLY95, SER96, VAL130, PRO131, TYR132, THR133, GLN134, ILE171, ILE179, ILE187, ALA188, ARG189, PRO190, TRP258, TYR259, ASP284, LYS285, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and ARG368, ±a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å;
- and
- (b) designing an agent using the three dimensional model generated in step (a).
A method for identifying an agent that interacts with an active site of an APP binding protein or peptide, comprising the steps of:
- (a) generating a three dimensional model of an active site of an APP binding protein or peptide using the relative structural coordinates according to FIG. 1 of residues LYS70, SER71, GLY72, GLN73, GLY74, TYR75, LEU91, VAL92, ASP93, THR94, GLY95, SER96, SER97, ASN98, TYR129, VAL130, PRO131, TYR132, THR133, GLN134, GLY135, LYS136, TRP137, LYS168, PHE169, PHE170, ILE171, ASN172, SER174, TRP176, GLY178, ILE179, LEU180, GLY181, ALA183, TYR184, ALA185, GLU186, ILE187, ALA188, ARG189, PRO190, ASP191, ASP192, ARG256, TRP258, TYR259, TYR283, ASP284, LYS285, SER286, ILE287, VAL288, ASP289, SER290, GLY291, THR292, THR293, ASN294, LEU295, ARG296, GLY325, GLU326, ARG368, VAL370, LYS382, PHE383, ALA384, ILE385, SER386, GLN387, SER388, SER389, THR390, GLY391, THR392, VAL393, GLY395, ALA396 and ILE447, ±a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å;
- and
- (b) designing an agent using the three dimensional model generated in step (a).
Dependencies are inferred from the claim text.