3D7V

Crystal structure of Mcl-1 in complex with an Mcl-1 selective BH3 ligand

3D7V の概要

• エントリーDOI: 10.2210/pdb3d7v/pdb
• 関連するPDBエントリー: 1WSX 2NL9 2NLA
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-like protein 11, ZINC ION, ... (4 entities in total)
• 機能のキーワード: helical bundle, amphipathic helix, alternative splicing, apoptosis, cytoplasm, developmental protein, differentiation, membrane, mitochondrion, nucleus, phosphoprotein, polymorphism, transmembrane, ubl conjugation
• 由来する生物種: Mus musculus (mouse, human); 詳細
• 細胞内の位置: Membrane ; Single-pass membrane protein : Q07820; Endomembrane system ; Peripheral membrane protein . Isoform BimEL: Mitochondrion. Isoform BimL: Mitochondrion. Isoform BimS: Mitochondrion. Isoform Bim-alpha1: Mitochondrion: O43521
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 21645.74

構造登録者

Lee, E.F.,Czabotar, P.E.,Colman, P.M.,Fairlie, W.D. (登録日: 2008-05-22, 公開日: 2008-06-24, 最終更新日: 2023-11-01)

主引用文献

Lee, E.F.,Czabotar, P.E.,van Delft, M.F.,Michalak, E.M.,Boyle, M.J.,Willis, S.N.,Puthalakath, H.,Bouillet, P.,Colman, P.M.,Huang, D.C.S.,Fairlie, W.D.
A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation.
J.Cell Biol., 180:341-355, 2008

PubMed Abstract: Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2-like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)-only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, Bim(S)2A, which is highly selective for Mcl-1. Unlike Noxa, Bim(S)2A is unable to trigger Mcl-1 degradation, yet, like Noxa, Bim(S)2A promotes cell killing only when Bcl-x(L) is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1.

PubMed: 18209102
DOI: 10.1083/jcb.200708096

実験手法

X-RAY DIFFRACTION (2.03 Å)