2i3h
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 2i3h |SIZE=350|CAPTION= <scene name='initialview01'>2i3h</scene>, resolution 1.62Å | |PDB= 2i3h |SIZE=350|CAPTION= <scene name='initialview01'>2i3h</scene>, resolution 1.62Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LI:LITHIUM+ION'>LI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= BIRC7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= BIRC7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1tw6|1TW6]], [[1oxn|1OXN]], [[1oxq|1OXQ]], [[1oy7|1OY7]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2i3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i3h OCA], [http://www.ebi.ac.uk/pdbsum/2i3h PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2i3h RCSB]</span> | ||
}} | }} | ||
| Line 24: | Line 27: | ||
[[Category: Fairbrother, W J.]] | [[Category: Fairbrother, W J.]] | ||
[[Category: Franklin, M C.]] | [[Category: Franklin, M C.]] | ||
| - | [[Category: BTB]] | ||
| - | [[Category: EDO]] | ||
| - | [[Category: LI]] | ||
| - | [[Category: ZN]] | ||
[[Category: apoptosis inhibition]] | [[Category: apoptosis inhibition]] | ||
[[Category: drug design]] | [[Category: drug design]] | ||
| Line 35: | Line 34: | ||
[[Category: zinc binding]] | [[Category: zinc binding]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:39:14 2008'' |
Revision as of 00:39, 31 March 2008
| |||||||
| , resolution 1.62Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , | ||||||
| Gene: | BIRC7 (Homo sapiens) | ||||||
| Related: | 1TW6, 1OXN, 1OXQ, 1OY7
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)
Overview
Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rationale is based on a combination of phage-panning data, peptide binding studies, and a survey of potential isosteres. The synthesis of two scaffolds is described. These compounds bind the XIAP-baculoviral IAP repeat 3 (BIR3), cIAP1-BIR3, cIAP2-BIR3, and ML-IAP-BIR domains with submicromolar affinities. The most potent Smac mimetic binds the cIAP1-BIR3 and ML-IAP-BIR domains with a K i of 50 nM. The X-ray crystal structure of this compound bound to an ML-IAP/XIAP chimeric BIR domain protein is compared with that of a complex with a phage-derived tetrapeptide, AVPW. The structures show that these compounds bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding patterns and similar hydrophobic interactions. Consistent with the structural data, coimmunoprecipitation experiments demonstrate that the compounds can effectively block Smac interactions with ML-IAP. The compounds are further demonstrated to activate caspase-3 and -7, to reduce cell viability in assays using MDA-MB-231 breast cancer cells and A2058 melanoma cells, and to enhance doxorubicin-induced apoptosis in MDA-MB-231 cells.
About this Structure
2I3H is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs., Zobel K, Wang L, Varfolomeev E, Franklin MC, Elliott LO, Wallweber HJ, Okawa DC, Flygare JA, Vucic D, Fairbrother WJ, Deshayes K, ACS Chem Biol. 2006 Sep 19;1(8):525-33. PMID:17168540
Page seeded by OCA on Mon Mar 31 03:39:14 2008
