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DOI | 10.1126/science.aat0572 |
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN | |
Sievers, Quinlan L.1,2; Petzold, Georg3; Bunker, Richard D.3; Renneville, Aline1,2; Slabicki, Mikolaj1,2,4,5; Liddicoat, Brian J.1,2; Abdulrahman, Wassim3,7; Mikkelsen, Tarjei1,8; Ebert, Benjamin L.1,2,6; Thoma, Nicolas H.3 | |
2018-11-02 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2018 |
卷号 | 362期号:6414页码:558-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Switzerland; Germany |
英文摘要 | The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys(2)-His(2) (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4(CRBN) E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000450460000038 |
WOS关键词 | UBIQUITIN LIGASE ; IKAROS ; GENE ; DEGRADATION ; RECRUITMENT ; COMPLEX ; KINASE |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/199989 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Broad Inst Harvard & MIT, Cambridge, MA 02142 USA; 2.Harvard Med Sch, Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA; 3.Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland; 4.Natl Ctr Tumor Dis, Div Translat Oncol, Heidelberg, Germany; 5.German Canc Res Ctr, D-69120 Heidelberg, Germany; 6.Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA; 7.LeadXpro AG Pk InnovAARE, CH-5232 Villigen, Switzerland; 8.10x Genom, 7068 Koll Ctr Pkwy 401, Pleasanton, CA 94566 USA |
推荐引用方式 GB/T 7714 | Sievers, Quinlan L.,Petzold, Georg,Bunker, Richard D.,et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN[J]. SCIENCE,2018,362(6414):558-+. |
APA | Sievers, Quinlan L..,Petzold, Georg.,Bunker, Richard D..,Renneville, Aline.,Slabicki, Mikolaj.,...&Thoma, Nicolas H..(2018).Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN.SCIENCE,362(6414),558-+. |
MLA | Sievers, Quinlan L.,et al."Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN".SCIENCE 362.6414(2018):558-+. |
条目包含的文件 | 条目无相关文件。 |
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