Abstract: Compounds that bind cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The compounds are mimetics of the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABOLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these compounds for therapeutic, diagnostic and assay purposes.

Abstract: Compounds that bind cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The compounds are mimetics of the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABOLO, IIid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these compounds for therapeutic, diagnostic and assay purposes.

Abstract: Atomic coordinates for human serine/threonine protein phosphotase 2A (PP2A) core, as well as methods for using these atomic coordinates to prepare inhibitors of PP2A and inhibitors prepared using such methods are provided herein. A biochemical analysis of the interactions of PP2A core is also provided. Compositions including mimetics and small molecules of the invention and, optionally, secondary agents may be used to treat disorders in which PP2A activity plays a contributing role.

Abstract: Atomic coordinates for human serine/threonine protein phosphotase 2A (PP2A) holoenzyme, as well as methods for using these atomic coordinates to prepare inhibitors of PP2A and inhibitors prepared using such methods are provided herein. A biochemical analysis of the interactions of PP2A holoenzyme is also provided. Compositions including mimetics and small molecules of the invention and, optionally, secondary agents may be used to treat disorders in which PP2A activity plays a contributing role.

Abstract: Embodiments of the present invention relate to atomic coordinates for PME-1 alone or in complex with PP2A, as well as methods for using these atomic coordinates to prepare inhibitors of PME-1 and/or PP2A and inhibitors prepared using such methods. Further embodiments relate to biochemical analyses of the interactions of PME-1 alone or in complex with PP2A. Further embodiments relate to compositions including mimetics and small molecules, optionally, secondary agents, which may be used to treat disorders in which PME-1 and/or PP2A activity plays a contributing role.

Abstract: The disclosure relates to modulation of protein phosphorylation, including information derived from the structures and activities of the proteins designated protein phosphatase 2A (PP2A) and PP2A methyl esterase. The disclosure contained herein provides compounds and methods for identification of compounds that antagonize the function of PME, and thus reduce levels of PP2A demethylation activity. Over-expression or gain-of-function of PME contributes to a range of diseases such as cancer, thus inhibition of PME by antagonists may provide a strategy for therapeutic intervention.

Abstract: Embodiments of the present invention relate to crystals and atomic coordinates for PP2A, as well as methods for using these atomic coordinates to prepare modulators of PP2A and inhibitors prepared using such methods. Further embodiments relate to biochemical analyses of the interactions of PP2A alone or in complex with Tau. Further embodiments relate to compositions including mimetics and small molecules, optionally, secondary agents, which may be used to treat disorders in which PP2A activity and/or Tau plays a contributing role.

Abstract: The present invention provides polypeptides and specific binding agents that modify the activity of an initiator caspase involved in apoptosis, caspase-9. The polypeptides include the third baculoviral IAP repeat (BIR3) of an IAP and form a heterodimer complex with caspase-9. Nucleic acid molecules including expression vectors encoding the polypeptides and variants thereof as well as variants of caspase-9 are provided. Such polypeptide and nucleic acid molecules may be used for modifying apoptosis.

Abstract: Structural models for a rhomboid protease alone and bound to inhibitors and peptide substrates and compositions and methods for preparing rhomboid protease binding compounds and methods for using such rhomboid protease binding compounds for modulation of these proteases catalytic activity are disclosed herein.

Abstract: Peptides and peptidomimetics capable of modulating apoptosis through their interaction with cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The peptides and mimetics are based on the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these peptides and peptidomimetics for therapeutic purposes and for rational drug design.

Abstract: The structure of a soluble, functional fragment of human Apaf-1 protein having ADP bound thereto is disclosed. The invention includes such soluble, functional fragments of human Apaf-1 and other metazoan Apaf-1 homologs. Also included in the invention are methods of making such fragments and methods of using them, for example in screening methods to identify adenine nucleotide analogs and other compounds useful for alleviating or preventing disease conditions associated with inappropriate regulation of apoptosis.

Abstract: Atomic coordinates for human phosphotyrosyl phosphatase activator (PTPA) and ATP?S bound by PTPA, as well as methods for using these atomic coordinates to prepare ATPase inhibitors of PTPA and ATPase inhibitors prepared using such methods are provided herein. Comprehensive biochemical analyses of the interactions of PTPA with ATP and protein phosphatase 2A are also provided. Compositions including mimetics and small molecules of the invention and, optionally, secondary agents may be used to treat disorders in which PTPA ATPase activity plays a contributing role.

Abstract: Embodiments of the present invention relate to the molecular interactions of Bcl-2 family members. The design of peptidomimetics that discriminate between anti-apoptotic and pro-apoptotic Bcl-2 family members and uses the same to modulate apoptosis are described herein.

Abstract: The disclosure relates to modulation of protein phosphorylation, including information derived from the structures and activities of the proteins designated protein phosphatase 2A (PP2A) and PP2A methyl esterase. The disclosure contained herein provides compounds and methods for identification of compounds that antagonize the function of PME, and thus reduce levels of PP2A demethylation activity. Over-expression or gain-of-function of PME contributes to a range of diseases such as cancer, thus inhibition of PME by antagonists may provide a strategy for therapeutic intervention.

Abstract: The disclosure contained herein provides compounds and methods for identification of compounds that agonize or antagonize the function of USP14, a member of the ubiquitin-specific processing protease (UBP) family. Over-expression or gain-of-function of UBP's contributes to a range of diseases such as cancer, thus inhibition of USP14 by antagonists may provide a strategy for therapeutic intervention. Loss-of-function or reduced expression of UBP's, or reduced expression of the proteasome, contributes to improper synaptic activity and neurodegenerative diseases, thus activation of USP14 by agonists may provide a strategy for therapeutic intervention.

Abstract: Peptides and peptidomimetics capable of modulating apoptosis through their interaction with cellular LAPs (inhibitor of apoptosis proteins) are disclosed. The peptides and mimetics are based on the N-terminal tetrapeptide of LAP-binding proteins, such as Smac/DLABLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these peptides and peptidomimetics for therapeutic purposes and for rational drug design.

Abstract: Compounds that bind cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The compounds are mimetics of the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABOLO, IIid. Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these compounds for therapeutic, diagnostic and assay purposes.

Abstract: The structure of a soluble, functional fragment of human Apaf-1 protein having ADP bound thereto is disclosed. The invention includes such soluble, functional fragments of human Apaf-1 and other metazoan Apaf-1 homologs. Also included in the invention are methods of making such fragments and methods of using them, for example in screening methods to identify adenine nucleotide analogs and other compounds useful for alleviating or preventing disease conditions associated with inappropriate regulation of apoptosis.

Abstract: Peptides and peptidomimetics capable of modulating apoptosis through their interaction with cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The peptides and mimetics are based on the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these peptides and peptidomimetics for therapeutic purposes and for rational drug design.

Abstract: Assays are disclosed for identifying peptides and peptidomimetics for promoting apotosis in cells, through a pathway involving the Inhibitor of Apoptosis Proteins (IAPs), exemplified by XIAP, and the mitochondrial protein Smac/DIABOLO (hereinafter Smac) and homologs thereof. Also disclosed are IAP-binding peptides and peptidomimetics identified through the use of the assay.