2i3h
From Proteopedia
(New page: 200px<br /> <applet load="2i3h" size="450" color="white" frame="true" align="right" spinBox="true" caption="2i3h, resolution 1.62Å" /> '''Structure of an ML-...) |
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| - | [[Image:2i3h.gif|left|200px]]<br /> | + | [[Image:2i3h.gif|left|200px]]<br /><applet load="2i3h" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2i3h" size=" | + | |
caption="2i3h, resolution 1.62Å" /> | caption="2i3h, resolution 1.62Å" /> | ||
'''Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)'''<br /> | '''Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Designed second mitochondrial activator of caspases (Smac) mimetics based | + | 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== | ==About this Structure== | ||
| - | 2I3H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, LI, BTB and EDO as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 2I3H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=LI:'>LI</scene>, <scene name='pdbligand=BTB:'>BTB</scene> and <scene name='pdbligand=EDO:'>EDO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I3H OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Fairbrother, W | + | [[Category: Fairbrother, W J.]] |
| - | [[Category: Franklin, M | + | [[Category: Franklin, M C.]] |
[[Category: BTB]] | [[Category: BTB]] | ||
[[Category: EDO]] | [[Category: EDO]] | ||
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[[Category: zinc binding]] | [[Category: zinc binding]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:48:41 2008'' |
Revision as of 15:48, 21 February 2008
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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 with , , and as ligands. 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 Thu Feb 21 17:48:41 2008
Categories: Homo sapiens | Single protein | Fairbrother, W J. | Franklin, M C. | BTB | EDO | LI | ZN | Apoptosis inhibition | Drug design | Peptide complex | Peptidomimetic | Small molecule | Zinc binding
