6GJW

Structure of XIAP-BIR1 domain in complex with an NF023 analog

6GJW の概要

• エントリーDOI: 10.2210/pdb6gjw/pdb
• 分子名称: E3 ubiquitin-protein ligase XIAP, ZINC ION, 4-[[3-[[3-[(4,8-disulfonatonaphthalen-1-yl)carbamoyl]phenyl]carbamoylamino]phenyl]carbonylamino]naphthalene-1,5-disulfonate, ... (4 entities in total)
• 機能のキーワード: bir; nf-kb; xiap; cancer; apoptosis; docking; inhibitor, apoptosis
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 51426.23

構造登録者

Sorrentino, L.,Cossu, F.,Malkoc, B.,Zaffaroni, M.,Milani, M.,Mastrangelo, E. (登録日: 2018-05-17, 公開日: 2019-05-29, 最終更新日: 2024-01-17)

主引用文献

Sorrentino, L.,Cossu, F.,Milani, M.,Malkoc, B.,Huang, W.C.,Tsay, S.C.,Ru Hwu, J.,Mastrangelo, E.
Structure-Activity Relationship of NF023 Derivatives Binding to XIAP-BIR1.
Chemistryopen, 8:476-482, 2019

PubMed 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.

PubMed: 31011505
DOI: 10.1002/open.201900059

実験手法

X-RAY DIFFRACTION (1.9 Å)