1tft: Difference between revisions
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|PDB= 1tft |SIZE=350|CAPTION= <scene name='initialview01'>1tft</scene> | |PDB= 1tft |SIZE=350|CAPTION= <scene name='initialview01'>1tft</scene> | ||
|SITE= | |SITE= | ||
|LIGAND= | |LIGAND= <scene name='pdbligand=997:1-[3,3-DIMETHYL-2-(2-METHYLAMINO-PROPIONYLAMINO)-BUTYRYL]-4-PHENOXY-PYRROLIDINE-2-CARBOXYLIC+ACID(1,2,3,4-TETRAHYDRO-NAPHTHALEN-1-YL)-AMIDE'>997</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= BIRC4, API3, IAP3, XIAP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= BIRC4, API3, IAP3, XIAP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
|DOMAIN= | |||
|RELATEDENTRY=[[1tfq|1tfq]], [[1g3f|1g3f]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1tft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tft OCA], [http://www.ebi.ac.uk/pdbsum/1tft PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1tft RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP. | Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Sun, C.]] | [[Category: Sun, C.]] | ||
[[Category: Zou, H.]] | [[Category: Zou, H.]] | ||
[[Category: apoptosis]] | [[Category: apoptosis]] | ||
[[Category: bir]] | [[Category: bir]] | ||
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[[Category: xiap]] | [[Category: xiap]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:55:29 2008'' | ||
