期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-33229-5
关键词
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资金
- National Key R&D Program of China [2019YFA0802401]
- NSERC [RGPIN-2021-02728]
- National Natural Science Foundation of China [32271309, 81773608]
- Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)
- CPRIT grant [RP180804]
- NIH [GM126421]
- Boehringer Ingelheim
- Bristol Myers Squibb
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant] [875510]
- Janssen
- Merck KGaA (aka EMD in Canada)
- Pfizer
- Takeda
- Northeastern Collaborative Access Team (NIGMS) [P30 GM124165]
- U.S. Department of Energy Office of Biological and Environmental Research [DE-AC02-06CH11357]
- Canada Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- University of Saskatchewan
- Government of Saskatchewan
- Western Economic Diversification Canada
- National Research Council Canada
- Canadian Institutes of Health Research
- Cancer Prevention Research Institute of Texas (CPRIT) [RP190682]
- Bayer AG
- Genentech
- Merck KGaA (aka EMD in US)
In this study, a potent and selective antagonist targeting the Tudor domain of SMN is reported, which disrupts the interaction between SMN and RNA Polymerase II, mimicking the effects of SMN deficiency.
Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN. The SMN protein recognizes symmetric dimethylarginine by its Tudor domain, and SMN deficiency leads to spinal muscular atrophy. Here, Liu et al. discover a small molecule that binds to the SMN Tudor domain and disrupts the interaction between SMN and RNA Polymerase II.
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