3KJ0

Mcl-1 in complex with Bim BH3 mutant I2dY

3KJ0 の概要

• エントリーDOI: 10.2210/pdb3kj0/pdb
• 関連するPDBエントリー: 2PQK 3KJ1 3KJ2
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-like protein 11, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• 機能のキーワード: bcl-2, bh3, apoptosis, protein-peptide complex, alternative splicing, cytoplasm, developmental protein, differentiation, isopeptide bond, membrane, mitochondrion, nucleus, phosphoprotein, polymorphism, transmembrane, ubl conjugation
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass membrane protein (Potential): Q07820; Endomembrane system; Peripheral membrane protein (By similarity). 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: 21238.97

構造登録者

Fire, E.,Grant, R.A.,Keating, A.E. (登録日: 2009-11-02, 公開日: 2010-02-16, 最終更新日: 2024-02-21)

主引用文献

Fire, E.,Gulla, S.V.,Grant, R.A.,Keating, A.E.
Mcl-1-Bim complexes accommodate surprising point mutations via minor structural changes.
Protein Sci., 19:507-519, 2010

PubMed Abstract: Mcl-1 is an antiapoptotic Bcl-2-family protein that protects cells against death. Structures of Mcl-1, and of other anti-apoptotic Bcl-2 proteins, reveal a surface groove into which the alpha-helical BH3 regions of certain proapoptotic proteins can bind. Despite high overall structural conservation, differences in this groove afford binding specificity that is important for the mechanism of Bcl-2 family function. We report the crystal structure of human Mcl-1 bound to a BH3 peptide derived from human Bim and the structures for three complexes that accommodate large physicochemical changes at conserved Bim sites. The mutations had surprisingly modest effects on complex stability, and the structures show that Mcl-1 can undergo small changes to accommodate the mutant ligands. For example, a shift in a leucine side chain fills a hole left by an isoleucine-to-alanine mutation at the first hydrophobic buried position of Bim BH3. Larger changes are also observed, with shifting of helix alpha3 accommodating an isoleucine-to-tyrosine mutation at this same position. We surveyed the variation in available Mcl-1 and Bcl-x(L) structures and observed moderate flexibility that is likely critical for facilitating interactions of diverse BH3-only proteins with Mcl-1. With the antiapoptotic Bcl-2 family members attracting significant attention as therapeutic targets, these structures contribute to our growing understanding of how specificity is achieved and can help to guide the design of novel inhibitors that target Mcl-1.

PubMed: 20066663
DOI: 10.1002/pro.329

実験手法

X-RAY DIFFRACTION (1.7 Å)