Max Planck Institute for Biology, Tübingen, Germany; Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany; NanoTemper Technologies GmbH, Munich, Germany.
Max Planck Institute for Biology, Tübingen, Germany.
Biochem Biophys Res Commun. 2023 Feb 26;646:30-35. doi: 10.1016/j.bbrc.2023.01.051. Epub 2023 Jan 18.
In targeted protein degradation, immunomodulatory drugs (IMiDs) or cereblon (CRBN) E3 ligase modulatory drugs (CELMoDs) recruit neo-substrate proteins to the E3 ubiquitin ligase receptor CRBN for ubiquitination and subsequent proteasomal degradation. While the structural basis of this mechanism is generally understood, we have only recently described the recognition mode of the natural CRBN degron. In this communication, we reveal that the IMiD- or CELMoD-mediated binding of neo-substrates closely mimics the recognition of natural degrons. In crystal structures, we identify a conserved binding mode for natural degron peptides with an elaborate hydrogen bonding network involving the backbone of each of the six C-terminal degron residues, without the involvement of side chains. In a structural comparison, we show that neo-substrates recruited by IMiDs or CELMoDs emulate every single hydrogen bond of this network and thereby explain the origins of the largely sequence-independent recognition of neo-substrates. Our results imply that the V388I substitution in CRBN does not impair natural degron recognition and complete the structural basis for the rational design of CRBN effectors.
在靶向蛋白降解中，免疫调节药物（IMiDs）或 cereblon（CRBN）E3 连接酶调节剂（CELMoDs）将新底物蛋白招募到 E3 泛素连接酶受体 CRBN 上进行泛素化和随后的蛋白酶体降解。虽然该机制的结构基础通常是理解的，但我们最近才描述了天然 CRBN 降解结构域的识别模式。在本通讯中，我们揭示了 IMiD 或 CELMoD 介导的新底物结合紧密模拟了天然降解结构域的识别。在晶体结构中，我们确定了天然降解结构域肽的保守结合模式，具有涉及每个六个 C 末端降解结构域残基的骨架的精细氢键网络，而不涉及侧链。在结构比较中，我们表明，由 IMiDs 或 CELMoDs 招募的新底物模拟了该网络的每一个氢键，从而解释了新底物的大部分序列非依赖性识别的起源。我们的结果表明，CRBN 中的 V388I 取代不会损害天然降解结构域的识别，并完成了合理设计 CRBN 效应物的结构基础。
