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Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1
Inhibitors of Apoptosis Proteins (IAPs) are conserved E3‐ligases that ubiquitylate substrates to prevent apoptosis and activate the NF‐kB survival pathway, often deregulated in cancer. IAPs‐mediated regulation of NF‐kB signaling is based on the formation of protein complexes by their type‐I BIR doma...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460348/ https://www.ncbi.nlm.nih.gov/pubmed/31011505 http://dx.doi.org/10.1002/open.201900059 |
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author | Sorrentino, Luca Cossu, Federica Milani, Mario Malkoc, Bilge Huang, Wen‐Chieh Tsay, Shwu‐Chen Ru Hwu, Jih Mastrangelo, Eloise |
author_facet | Sorrentino, Luca Cossu, Federica Milani, Mario Malkoc, Bilge Huang, Wen‐Chieh Tsay, Shwu‐Chen Ru Hwu, Jih Mastrangelo, Eloise |
author_sort | Sorrentino, Luca |
collection | PubMed |
description | Inhibitors of Apoptosis Proteins (IAPs) are conserved E3‐ligases that ubiquitylate substrates to prevent apoptosis and activate the NF‐kB survival pathway, often deregulated in cancer. IAPs‐mediated regulation of NF‐kB signaling is based on the formation of protein complexes by their type‐I BIR domains. The XIAP‐BIR1 domain dimerizes to bind two TAB1 monomers, leading to downstream NF‐kB activation. Thus, impairment of XIAP‐BIR1 dimerization could represent a novel strategy to hamper cell survival in cancer. To this aim, we previously reported NF023 as a potential inhibitor of XIAP‐BIR1 dimerization. Here we present a thorough analysis of NF023 binding to XIAP‐BIR1 through biochemical, biophysical and structural data. The results obtained indicate that XIAP‐BIR1 dimerization interface is involved in NF023 binding, and that NF023 overall symmetry and the chemical features of its central moiety are essential for an efficient interaction with the protein. Such strategy provides original hints for the development of novel BIR1‐specific compounds as pro‐apoptotic agents. |
format | Online Article Text |
id | pubmed-6460348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64603482019-04-22 Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 Sorrentino, Luca Cossu, Federica Milani, Mario Malkoc, Bilge Huang, Wen‐Chieh Tsay, Shwu‐Chen Ru Hwu, Jih Mastrangelo, Eloise ChemistryOpen Full Papers Inhibitors of Apoptosis Proteins (IAPs) are conserved E3‐ligases that ubiquitylate substrates to prevent apoptosis and activate the NF‐kB survival pathway, often deregulated in cancer. IAPs‐mediated regulation of NF‐kB signaling is based on the formation of protein complexes by their type‐I BIR domains. The XIAP‐BIR1 domain dimerizes to bind two TAB1 monomers, leading to downstream NF‐kB activation. Thus, impairment of XIAP‐BIR1 dimerization could represent a novel strategy to hamper cell survival in cancer. To this aim, we previously reported NF023 as a potential inhibitor of XIAP‐BIR1 dimerization. Here we present a thorough analysis of NF023 binding to XIAP‐BIR1 through biochemical, biophysical and structural data. The results obtained indicate that XIAP‐BIR1 dimerization interface is involved in NF023 binding, and that NF023 overall symmetry and the chemical features of its central moiety are essential for an efficient interaction with the protein. Such strategy provides original hints for the development of novel BIR1‐specific compounds as pro‐apoptotic agents. John Wiley and Sons Inc. 2019-04-12 /pmc/articles/PMC6460348/ /pubmed/31011505 http://dx.doi.org/10.1002/open.201900059 Text en ©2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Full Papers Sorrentino, Luca Cossu, Federica Milani, Mario Malkoc, Bilge Huang, Wen‐Chieh Tsay, Shwu‐Chen Ru Hwu, Jih Mastrangelo, Eloise Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 |
title | Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 |
title_full | Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 |
title_fullStr | Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 |
title_full_unstemmed | Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 |
title_short | Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 |
title_sort | structure‐activity relationship of nf023 derivatives binding to xiap‐bir1 |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460348/ https://www.ncbi.nlm.nih.gov/pubmed/31011505 http://dx.doi.org/10.1002/open.201900059 |
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