Defining molecular glues with a dual-nanobody cannabidiol sensor.
Defining molecular glues with a dual-nanobody cannabidiol sensor.
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用双纳米体大麻二酚传感器定义分子胶。
DOI：
10.1038/s41467-022-28507-1
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发表时间：
2022-02-10
影响因子：
16.6
通讯作者：
Zheng N
中科院分区：
文献类型：
--
作者：
Cao S;Kang S;Mao H;Yao J;Gu L;Zheng N
“分子胶”（MG）是一个术语，旨在描述植物骑士生长素的作用机理，随后用来表征合成的小分子蛋白降解器，例如，通过其前瞻性开发了MG的前瞻性，并在此报告了晶体的晶体，并以晶体的形式进行了预期。配体促进的系统蛋白质蛋白质的相互作用类似于生长素。至少一个蛋白质伴侣中的igand结合活性和一个两种蛋白质亚基之间的低微摩尔亲和力已被配体增强以达到纳莫尔范围的情况，这两个统一特征将MGS定义为特殊的接近性诱导剂，这些特征与双功能化合物不同，可以用作指导目标选择的标准。
分子胶已被用作一个描述一类蛋白质相互作用的化合物的广泛术语，作者概述了两个统一的热力学特征，以正式定义分子胶并指导其前瞻性发现。
“Molecular glue” (MG) is a term coined to describe the mechanism of action of the plant hormone auxin and subsequently used to characterize synthetic small molecule protein degraders exemplified by immune-modulatory imide drugs (IMiDs). Prospective development of MGs, however, has been hampered by its elusive definition and thermodynamic characteristics. Here, we report the crystal structure of a dual-nanobody cannabidiol-sensing system, in which the ligand promotes protein-protein interaction in a manner analogous to auxin. Through quantitative analyses, we draw close parallels among the dual-nanobody cannabidiol sensor, the auxin perception complex, and the IMiDs-bound CRL4CRBN E3, which can bind and ubiquitinate “neo-substrates”. All three systems, including the recruitment of IKZF1 and CK1α to CRBN, are characterized by the lack of ligand binding activity in at least one protein partner and an under-appreciated preexisting low micromolar affinity between the two proteinaceous subunits that is enhanced by the ligand to reach the nanomolar range. These two unifying features define MGs as a special class of proximity inducers distinct from bifunctional compounds and can be used as criteria to guide target selection for future rational discovery of MGs. Molecular glue has been used as a broad term describing a class of protein interaction-promoting compounds. Here, the authors outline two unifying thermodynamic features to formally define molecular glues and guide their prospective discovery.
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