4K5B

Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W

4K5B の概要

• エントリーDOI: 10.2210/pdb4k5b/pdb
• 関連するPDBエントリー: 4K5A
• 分子名称: Apoptosis regulator BCL-W, Bcl-2-like protein 2 (3 entities in total)
• 機能のキーワード: apoptosis, anti-apoptotic bcl-2 family, bcl-w;crystal structure, ligand binding-competent conformation, darpins
• 由来する生物種: Escherichia coli; 詳細
• 細胞内の位置: Mitochondrion membrane; Peripheral membrane protein (By similarity): 4K5B
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 76808.17

構造登録者

Schilling, J.,Schoeppe, J.,Sauer, E.,Plueckthun, A. (登録日: 2013-04-14, 公開日: 2014-04-16, 最終更新日: 2024-03-20)

主引用文献

Schilling, J.,Schoppe, J.,Sauer, E.,Pluckthun, A.
Co-Crystallization with Conformation-Specific Designed Ankyrin Repeat Proteins Explains the Conformational Flexibility of BCL-W
J.Mol.Biol., 426:2346-2362, 2014

PubMed Abstract: BCL-W is a member of the BCL-2 family of anti-apoptotic proteins. A key event in the regulation of apoptosis is the heterodimerization between anti-apoptotic and pro-apoptotic family members, which involves a conserved surface-exposed groove on the anti-apoptotic proteins. Crystal structures of the ligand binding-competent conformation exist for all anti-apoptotic family members, with the exception of BCL-W, due to the flexibility of the BCL-W groove region. Existing structures had suggested major deviations of the BCL-W groove region from the otherwise structurally highly related remaining anti-apoptotic family members. To capture its ligand binding-competent conformation by counteracting the conformational flexibility of the BCL-W groove, we had selected high-affinity groove-binding designed ankyrin repeat proteins (DARPins) using ribosome display. We now determined two high-resolution crystal structures of human BCL-W in complex with different DARPins at resolutions 1.5 and 1.85Å, in which the structure of BCL-W is virtually identical, and BCL-W adopts a conformation extremely similar to the ligand-free conformation of its closest relative BCL-XL in both structures. However, distinct differences to all previous BCL-W structures are evident, notably in the ligand-binding region. We provide the first structural explanation for the conformational flexibility of the BCL-W groove region in comparison to other BCL-2 family members. Due to the importance of the anti-apoptotic BCL-2 family as drug targets, the presented crystal structure of ligand binding-competent BCL-W may serve as a valuable basis for structure-based drug design in the future and provides a missing piece for the structural characterization of this protein family.

PubMed: 24747052
DOI: 10.1016/j.jmb.2014.04.010

実験手法

X-RAY DIFFRACTION (1.85 Å)