Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1
Abstract 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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley-VCH
2019-04-01
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| Series: | ChemistryOpen |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/open.201900059 |
| _version_ | 1797771191955488768 |
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| author | Dr. Luca Sorrentino Dr. Federica Cossu Dr. Mario Milani Bilge Malkoc Dr. Wen‐Chieh Huang Dr. Shwu‐Chen Tsay Prof. Jih Ru Hwu Dr. Eloise Mastrangelo |
| author_facet | Dr. Luca Sorrentino Dr. Federica Cossu Dr. Mario Milani Bilge Malkoc Dr. Wen‐Chieh Huang Dr. Shwu‐Chen Tsay Prof. Jih Ru Hwu Dr. Eloise Mastrangelo |
| author_sort | Dr. Luca Sorrentino |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-12T21:33:56Z |
| format | Article |
| id | doaj.art-d101b2a1573a4942aecfcd622ee5a7b2 |
| institution | Directory Open Access Journal |
| issn | 2191-1363 |
| language | English |
| last_indexed | 2024-03-12T21:33:56Z |
| publishDate | 2019-04-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | ChemistryOpen |
| spelling | doaj.art-d101b2a1573a4942aecfcd622ee5a7b22023-07-27T14:18:23ZengWiley-VCHChemistryOpen2191-13632019-04-018447648210.1002/open.201900059Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1Dr. Luca Sorrentino0Dr. Federica Cossu1Dr. Mario Milani2Bilge Malkoc3Dr. Wen‐Chieh Huang4Dr. Shwu‐Chen Tsay5Prof. Jih Ru Hwu6Dr. Eloise Mastrangelo7CNR-IBF Via Celoria 26 I-20133 Milano ItalyCNR-IBF Via Celoria 26 I-20133 Milano ItalyCNR-IBF Via Celoria 26 I-20133 Milano ItalyDepartment of Biosciences Università di Milano Via Celoria 26 I-20133 Milano ItalyDepartment of Chemistry & Frontier Research Center on Fundamental and Applied Sciences of Matters National Tsing Hua University Hsinchu 30013 TaiwanDepartment of Chemistry & Frontier Research Center on Fundamental and Applied Sciences of Matters National Tsing Hua University Hsinchu 30013 TaiwanDepartment of Chemistry & Frontier Research Center on Fundamental and Applied Sciences of Matters National Tsing Hua University Hsinchu 30013 TaiwanCNR-IBF Via Celoria 26 I-20133 Milano ItalyAbstract 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.https://doi.org/10.1002/open.201900059apoptosisdrug discoverystructure-activity relationshipin silico dockingprotein structures |
| spellingShingle | Dr. Luca Sorrentino Dr. Federica Cossu Dr. Mario Milani Bilge Malkoc Dr. Wen‐Chieh Huang Dr. Shwu‐Chen Tsay Prof. Jih Ru Hwu Dr. Eloise Mastrangelo Structure‐Activity Relationship of NF023 Derivatives Binding to XIAP‐BIR1 ChemistryOpen apoptosis drug discovery structure-activity relationship in silico docking protein structures |
| 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 | apoptosis drug discovery structure-activity relationship in silico docking protein structures |
| url | https://doi.org/10.1002/open.201900059 |
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