| pubmed-article:19393243 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:19393243 | lifeskim:mentions | umls-concept:C0524637 | lld:lifeskim |
| pubmed-article:19393243 | lifeskim:mentions | umls-concept:C0893445 | lld:lifeskim |
| pubmed-article:19393243 | lifeskim:mentions | umls-concept:C0678594 | lld:lifeskim |
| pubmed-article:19393243 | lifeskim:mentions | umls-concept:C1527178 | lld:lifeskim |
| pubmed-article:19393243 | lifeskim:mentions | umls-concept:C1335532 | lld:lifeskim |
| pubmed-article:19393243 | pubmed:issue | 3 | lld:pubmed |
| pubmed-article:19393243 | pubmed:dateCreated | 2009-9-7 | lld:pubmed |
| pubmed-article:19393243 | pubmed:databankReference | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:abstractText | XIAP is an apoptotic regulator protein that binds to the effector caspases -3 and -7 through its BIR2 domain, and to initiator caspase-9 through its BIR3 domain. Molecular docking studies suggested that Smac-DIABLO may antagonize XIAP by concurrently targeting both BIR2 and BIR3 domains; on this basis bivalent Smac-mimetic compounds have been proposed and characterized. Here, we report the X-ray crystal structure of XIAP-BIR3 domain in complex with a two-headed compound (compound 3) with improved efficacy relative to its monomeric form. A small-angle X-ray scattering study of XIAP-BIR2BIR3, together with fluorescence polarization binding assays and compound 3 cytotoxicity tests on HL60 leukemia cell line are also reported. The crystal structure analysis reveals a network of interactions supporting XIAP-BIR3/compound 3 recognition; moreover, analytical gel-filtration chromatography shows that compound 3 forms a 1:1 stoichiometric complex with a XIAP protein construct containing both BIR2 and BIR3 domains. On the basis of the crystal structure and small-angle X-ray scattering, a model of the same BIR2-BIR3 construct bound to compound 3 is proposed, shedding light on the ability of compound 3 to relieve XIAP inhibitory effects on caspase-9 as well as caspases -3 and -7. A molecular modeling/docking analysis of compound 3 bound to cIAP1-BIR3 domain is presented, considering that Smac-mimetics have been shown to kill tumor cells by inducing cIAP1 and cIAP2 ubiquitination and degradation. Taken together, the results reported here provide a rationale for further development of compound 3 as a lead in the design of dimeric Smac mimetics for cancer treatment. | lld:pubmed |
| pubmed-article:19393243 | pubmed:language | eng | lld:pubmed |
| pubmed-article:19393243 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:19393243 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19393243 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:19393243 | pubmed:month | Sep | lld:pubmed |
| pubmed-article:19393243 | pubmed:issn | 1089-8638 | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:BolognesiMart... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:VachettePatri... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:MilaniMarioM | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:ServidaFederi... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:RizzoVincenzo... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:DeliaDomenico... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:ScolasticoCar... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:LecisDanieleD | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:ManzoniLeonar... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:SeneciPierfau... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:DragoCarmeloC | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:MastrangeloEl... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:CossuFederica... | lld:pubmed |
| pubmed-article:19393243 | pubmed:author | pubmed-author:CanevariGiuli... | lld:pubmed |
| pubmed-article:19393243 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:19393243 | pubmed:day | 25 | lld:pubmed |
| pubmed-article:19393243 | pubmed:volume | 392 | lld:pubmed |
| pubmed-article:19393243 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:19393243 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:19393243 | pubmed:pagination | 630-44 | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:meshHeading | pubmed-meshheading:19393243... | lld:pubmed |
| pubmed-article:19393243 | pubmed:year | 2009 | lld:pubmed |
| pubmed-article:19393243 | pubmed:articleTitle | Structural basis for bivalent Smac-mimetics recognition in the IAP protein family. | lld:pubmed |
| pubmed-article:19393243 | pubmed:affiliation | Department of Biomolecular Sciences and Biotechnology, University of Milano, Italy. | lld:pubmed |
| pubmed-article:19393243 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:19393243 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
| entrez-gene:331 | entrezgene:pubmed | pubmed-article:19393243 | lld:entrezgene |
| http://linkedlifedata.com/r... | entrezgene:pubmed | pubmed-article:19393243 | lld:entrezgene |
| http://linkedlifedata.com/r... | pubmed:referesTo | pubmed-article:19393243 | lld:pubmed |
