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Nature, 12 February 2025 | https://doi.org/10.1038/s41586-024-08532-4
UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors
Megan J. R. Yeo 1,2,12, Olivia Zhang 1,2,12, Xiaowen Xie 3,4,12, Eunju Nam 5,12, N. Connor Payne 1,6,7, Pallavi M. Gosavi 1,2, Hui Si Kwok 1,2, Irtiza Iram 1,2, Ceejay Lee 1,2, Jiaming Li 1,2, Nicholas J. Chen 1,2,8, Khanh Nguyen 2, Hanjie Jiang 5, Zhipeng A. Wang 5,11, Kwangwoon Lee 5, Haibin Mao 3,4, Stefan A. Harry 1,2,8, Idris A. Barakat 1,2, Mariko Takahashi 8, Amanda L. Waterbury 1,2,Marco Barone 9, Andrea Mattevi 9, Steven A. Carr 2, Namrata D. Udeshi 2, Liron Bar-Peled 8,10, Philip A. Cole 5, Ralph Mazitschek 2,6,7, Brian B. Liau 1,2,* & Ning Zheng 3,4,*
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3Department of Pharmacology, University of Washington, Seattle, WA, USA.
4Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
5Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
6Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
7Harvard T.H. Chan School of Public Health, Boston, MA, USA.
8Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
9Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy.
10Department of Medicine, Harvard Medical School, Boston, MA, USA.
11Present address: Desai Sethi Urology Institute & Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
12These authors contributed equally: Megan J. R. Yeo, Olivia Zhang, Xiaowen Xie, Eunju Nam.
2Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3Department of Pharmacology, University of Washington, Seattle, WA, USA.
4Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
5Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
6Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
7Harvard T.H. Chan School of Public Health, Boston, MA, USA.
8Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
9Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Pavia, Italy.
10Department of Medicine, Harvard Medical School, Boston, MA, USA.
11Present address: Desai Sethi Urology Institute & Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
12These authors contributed equally: Megan J. R. Yeo, Olivia Zhang, Xiaowen Xie, Eunju Nam.
*Corresponding authors: correspondence to Brian B. Liau or Ning Zheng
Abstract
UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal. By co-opting KBTBD4, a substrate receptor of the CUL3–RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1–CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1–HDAC1–CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3–neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST–HDAC1/2–KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-14)
- 국외 연구진
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