6R1C

Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with compound 12a

6R1C の概要

• エントリーDOI: 10.2210/pdb6r1c/pdb
• 分子名称: Cereblon isoform 4, ASPARTIC ACID, ZINC ION, ... (8 entities in total)
• 機能のキーワード: proteolysis targeting chimera, protac, protein degradation, signaling protein
• 由来する生物種: Magnetospirillum gryphiswaldense MSR-1
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 42654.23

構造登録者

Heim, C.,Hartmann, M.D. (登録日: 2019-03-14, 公開日: 2019-08-07, 最終更新日: 2024-01-24)

主引用文献

Heim, C.,Pliatsika, D.,Mousavizadeh, F.,Bar, K.,Hernandez Alvarez, B.,Giannis, A.,Hartmann, M.D.
De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives.
J.Med.Chem., 62:6615-6629, 2019

PubMed Abstract: Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.

PubMed: 31251063
DOI: 10.1021/acs.jmedchem.9b00454

実験手法

X-RAY DIFFRACTION (1.5 Å)