A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.

Autor: Liu Y; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China. ylliu18@suda.edu.cn.; Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China. ylliu18@suda.edu.cn.; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada. ylliu18@suda.edu.cn., Iqbal A; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Li W; Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China.; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Ni Z; Donnelly Centre, University of Toronto, Toronto, ON, Canada., Wang Y; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ramprasad J; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Abraham KJ; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Zhang M; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Zhao DY; Donnelly Centre, University of Toronto, Toronto, ON, Canada., Qin S; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.; Life Science Research Center, Southern University of Science and Technology, Shenzhen, Guangdong, China., Loppnau P; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Jiang H; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Guo X; Donnelly Centre, University of Toronto, Toronto, ON, Canada., Brown PJ; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Zhen X; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Xu G; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Mekhail K; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Ji X; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China., Bedford MT; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Greenblatt JF; Donnelly Centre, University of Toronto, Toronto, ON, Canada., Min J; Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China. minjinrong@ccnu.edu.cn.; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada. minjinrong@ccnu.edu.cn.; Department of Physiology, University of Toronto, Toronto, ON, Canada. minjinrong@ccnu.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Sep 16; Vol. 13 (1), pp. 5453. Date of Electronic Publication: 2022 Sep 16.
DOI: 10.1038/s41467-022-33229-5
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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