Template-assisted covalent modification underlies activity of covalent molecular glues

IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Nature chemical biology Pub Date : 2024-07-29 DOI:10.1038/s41589-024-01668-4
Yen-Der Li, Michelle W. Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine C. Rutter, Ryan J. Lumpkin, Brittany Sandoval, Cyrus Y. Jin, Anna M. Schmoker, Scott B. Ficarro, Hakyung Cheong, Rebecca J. Metivier, Michelle Y. Wang, Shawn Xu, Woong Sub Byun, Brian J. Groendyke, Inchul You, Logan H. Sigua, Isidoro Tavares, Charles Zou, Jonathan M. Tsai, Paul M. C. Park, Hojong Yoon, Felix C. Majewski, Haniya T. Sperling, Jarrod A. Marto, Jun Qi, Radosław P. Nowak, Katherine A. Donovan, Mikołaj Słabicki, Nathanael S. Gray, Eric S. Fischer, Benjamin L. Ebert
{"title":"Template-assisted covalent modification underlies activity of covalent molecular glues","authors":"Yen-Der Li, Michelle W. Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine C. Rutter, Ryan J. Lumpkin, Brittany Sandoval, Cyrus Y. Jin, Anna M. Schmoker, Scott B. Ficarro, Hakyung Cheong, Rebecca J. Metivier, Michelle Y. Wang, Shawn Xu, Woong Sub Byun, Brian J. Groendyke, Inchul You, Logan H. Sigua, Isidoro Tavares, Charles Zou, Jonathan M. Tsai, Paul M. C. Park, Hojong Yoon, Felix C. Majewski, Haniya T. Sperling, Jarrod A. Marto, Jun Qi, Radosław P. Nowak, Katherine A. Donovan, Mikołaj Słabicki, Nathanael S. Gray, Eric S. Fischer, Benjamin L. Ebert","doi":"10.1038/s41589-024-01668-4","DOIUrl":null,"url":null,"abstract":"<p>Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a <i>trans</i>-labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4<sup>DCAF16</sup> ligase to the second bromodomain of BRD4 (BRD4<sub>BD2</sub>). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4<sub>BD2</sub> serves as a template to optimally orient the degrader for covalent modification of DCAF16<sub>Cys58</sub>. This process stabilizes the formation of BRD4–degrader–DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK–BRD4<sub>BD2</sub> interaction through <i>trans</i>-labeling of GAK. Together, our work establishes ‘template-assisted covalent modification’ as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology.</p><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":null,"pages":null},"PeriodicalIF":12.9000,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature chemical biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41589-024-01668-4","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes the formation of BRD4–degrader–DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK–BRD4BD2 interaction through trans-labeling of GAK. Together, our work establishes ‘template-assisted covalent modification’ as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
模板辅助共价修饰是共价分子胶活性的基础
分子粘合剂是一种诱导接近的小分子,已成为一种极具吸引力的治疗方法。然而,分子胶的开发仍然充满挑战,需要创新的机制策略来稳定新蛋白界面并加速发现。在这里,我们揭示了一种称为 "模板辅助共价修饰 "的反式标记共价分子胶合机制。我们发现了一系列新的 BRD4 分子胶降解剂,它们能将 CUL4DCAF16 连接酶招募到 BRD4 的第二个溴结构域(BRD4BD2)。通过全面的生化、结构和诱变分析,我们阐明了 DCAF16 和 BRD4BD2 之间预先存在的结构互补性如何作为模板,优化降解器的方向,对 DCAF16Cys58 进行共价修饰。这一过程稳定了BRD4-降解剂-DCAF16三元复合物的形成,促进了BRD4的降解。我们发现,一个降解子集也能通过反式标记 GAK 来诱导 GAK-BRD4BD2 相互作用,这证明了降解的普遍性。总之,我们的工作确立了 "模板辅助共价修饰 "作为共价分子胶合剂的一种机制,为近距离驱动药理学开辟了一条新路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Nature chemical biology
Nature chemical biology 生物-生化与分子生物学
CiteScore
23.90
自引率
1.40%
发文量
238
审稿时长
12 months
期刊介绍: Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.
期刊最新文献
Engineering a xylose fermenting yeast for lignocellulosic ethanol production A multiplex single-cell RNA-Seq pharmacotranscriptomics pipeline for drug discovery Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion Evading resistance at the double Protein Degradation in Focus
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1