3INQ

Crystal structure of BCL-XL in complex with W1191542

3INQ の概要

• エントリーDOI: 10.2210/pdb3inq/pdb
• 関連するPDBエントリー: 2P1L 2YXJ 3FDL 3IO8 3IO9
• 分子名称: Bcl-2-like protein 1, 4-[4-(biphenyl-3-ylmethyl)piperazin-1-yl]-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylsulfanyl)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}benzamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: apoptosis, alternative splicing, membrane, mitochondrion, nucleus, transmembrane
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Isoform Bcl-X(L): Mitochondrion inner membrane : Q07817
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38112.08

構造登録者

Fairlie, W.D.,Smith, B.J.,Colman, P.M.,Czabotar, P.E.,Lee, E.F. (登録日: 2009-08-12, 公開日: 2009-09-01, 最終更新日: 2023-11-01)

主引用文献

Lee, E.F.,Czabotar, P.E.,Yang, H.,Sleebs, B.E.,Lessene, G.,Colman, P.M.,Smith, B.J.,Fairlie, W.D.
Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands
J. Biol. Chem., 284:30508-30517, 2009

PubMed Abstract: Antagonists of anti-apoptotic Bcl-2 family members hold promise as cancer therapeutics. Apoptosis is triggered when a peptide containing a BH3 motif or a small molecule BH3 peptidomimetic, such as ABT 737, binds to the relevant Bcl-2 family members. ABT-737 is an antagonist of Bcl-2, Bcl-x(L), and Bcl-w but not of Mcl-1. Here we describe new structures of mutant BH3 peptides bound to Bcl-x(L) and Mcl-1. These structures suggested a rationale for the failure of ABT-737 to bind Mcl-1, but a designed variant of ABT-737 failed to acquire binding affinity for Mcl-1. Rather, it was selective for Bcl-x(L), a result attributable in part to significant backbone refolding and movements of helical segments in its ligand binding site. To date there are few reported crystal structures of organic ligands in complex with their pro-survival protein targets. Our structure of this new organic ligand provided insights into the structural transitions that occur within the BH3 binding groove, highlighting significant differences in the structural properties of members of the Bcl-2 pro-survival protein family. Such differences are likely to influence and be important in the quest for compounds capable of selectively antagonizing the different family members.

PubMed: 19726685
DOI: 10.1074/jbc.M109.040725

実験手法

X-RAY DIFFRACTION (2 Å)