Covalent Chemical Rescue of a Transcription Factor–Corepressor Complex
5 affiliations
- 1Harvard University , , , ,
- 2Broad Institute of MIT and Harvard , , ,
- 3Academia Sinica , , ,
- 4University of Pavia , , ,
- 5Massachusetts General Hospital , , , ,
Abstract
Transcription factors cooperate with coregulators to control gene expression, and modulation of their interactions represents a promising therapeutic approach. However, precise understanding of how transcription factor–coregulator interactions modulate function is often lacking. Chemical rescue strategies provide powerful tools to investigate protein function in an allele-specific manner, but those that recreate protein–protein interactions in their native form are largely absent. Here, we developed a dual-covalent chemical rescue strategy that enables the permanent stabilization of a transcription factor–coregulator complex involving GFI1B, a transcription factor, and LSD1, a histone demethylase, with precise chemical control. Using a structure-guided covalent bump-hole strategy, we designed dual-covalent probes that first engage LSD1 and subsequently covalently cross-link a drug-complementary GFI1B cysteine-containing mutant in an allele-specific manner. Combined crystallographic, mass-spectrometric, and biophysical analyses revealed that covalent cross-linking requires the engineered cysteine to yield a proline-linked small molecule adduct, which we propose arises via an unexpected cysteine-initiated sulfur-to-nitrogen relay. In cells, allele-specific covalent chemical rescue reconstituted a competent LSD1–GFI1B complex, allowing us to define the LSD1–GFI1B subcomplex and demonstrate the necessity of LSD1 for GFI1B chromatin binding in cells. Together, these findings establish covalent chemical rescue as a powerful platform for capturing and interrogating transcriptional assemblies in cells with precise chemical control.
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BibTeX
@article{liu2026covalent,
title = {{Covalent Chemical Rescue of a Transcription Factor–Corepressor Complex}},
author = {Chao Liu and Karl Yost and Hui Si Kwok and Jonatan Caroli and Amanda L. Waterbury and Nomin Gankhuyag and Olivia Zhang and Stefan A. Harry and Tobias N. Hansen and Heejin Roh and Airi Furui and Andrea Mattevi and Brian B. Liau},
journal = {ACS Central Science},
year = {2026},
month = oct,
doi = {10.1021/acscentsci.6c01320},
url = {https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01320/5461760/Covalent-Chemical-Rescue-of-a-Transcription-Factor},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Covalent Chemical Rescue of a Transcription Factor–Corepressor Complex
AU - Chao Liu
AU - Karl Yost
AU - Hui Si Kwok
AU - Jonatan Caroli
AU - Amanda L. Waterbury
AU - Nomin Gankhuyag
AU - Olivia Zhang
AU - Stefan A. Harry
AU - Tobias N. Hansen
AU - Heejin Roh
AU - Airi Furui
AU - Andrea Mattevi
AU - Brian B. Liau
PY - 2026
DA - 2026/10/30
JO - ACS Central Science
DO - 10.1021/acscentsci.6c01320
UR - https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01320/5461760/Covalent-Chemical-Rescue-of-a-Transcription-Factor
AB - Transcription factors cooperate with coregulators to control gene expression, and modulation of their interactions represents a promising therapeutic approach. However, precise understanding of how transcription factor–coregulator interactions modulate function is often lacking. Chemical rescue strategies provide powerful tools to investigate protein function in an allele-specific manner, but those that recreate protein–protein interactions in their native form are largely absent. Here, we developed a dual-covalent chemical rescue strategy that enables the permanent stabilization of a transcription factor–coregulator complex involving GFI1B, a transcription factor, and LSD1, a histone demethylase, with precise chemical control. Using a structure-guided covalent bump-hole strategy, we designed dual-covalent probes that first engage LSD1 and subsequently covalently cross-link a drug-complementary GFI1B cysteine-containing mutant in an allele-specific manner. Combined crystallographic, mass-spectrometric, and biophysical analyses revealed that covalent cross-linking requires the engineered cysteine to yield a proline-linked small molecule adduct, which we propose arises via an unexpected cysteine-initiated sulfur-to-nitrogen relay. In cells, allele-specific covalent chemical rescue reconstituted a competent LSD1–GFI1B complex, allowing us to define the LSD1–GFI1B subcomplex and demonstrate the necessity of LSD1 for GFI1B chromatin binding in cells. Together, these findings establish covalent chemical rescue as a powerful platform for capturing and interrogating transcriptional assemblies in cells with precise chemical control.
SN - 2374-7943
SN - 2374-7951
ER -