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

Liu，Yanli1,2,3; Iqbal，Aman3; Li，Weiguo2,3; Ni，Zuyao4; Wang，Yalong5; Ramprasad，Jurupula1; Abraham，Karan Joshua6; Zhang，Mengmeng1; Zhao，Dorothy Yanling4; Qin，Su3,7; Loppnau，Peter3; Jiang，Honglv1; Guo，Xinghua4; Brown，Peter J.3; Zhen，Xuechu1; Xu，Guoqiang1; Mekhail，Karim6; Ji，Xingyue1; Bedford，Mark T.5; Greenblatt，Jack F.4; Min，Jinrong2,3,8

2022-12-01

10.1038/s41467-022-33229-5

Nature Communications   Impact Factor & Quartile

2041-1723

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.

SCI

English

NI Journal Papers

Others

National Outstanding Youth Science Fund Project of National Natural Science Foundation of China[31500615];Natural Sciences and Engineering Research Council of Canada[RGPIN-2021-02728];

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000854793700019

NATURE PORTFOLIO

2-s2.0-85138187363

Scopus

1.Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences,Soochow University,Suzhou,Jiangsu,China
2.Hubei Key Laboratory of Genetic Regulation and Integrative Biology,School of Life Sciences,Central China Normal University,Wuhan,Hubei,China
3.Structural Genomics Consortium,University of Toronto,Toronto,Canada
4.Donnelly Centre,University of Toronto,Toronto,Canada
5.Department of Epigenetics and Molecular Carcinogenesis,The University of Texas MD Anderson Cancer Center,Houston,United States
6.Department of Laboratory Medicine and Pathobiology,Faculty of Medicine,University of Toronto,Toronto,Canada
7.Life Science Research Center,Southern University of Science and Technology,Shenzhen,Guangdong,China
8.Department of Physiology,University of Toronto,Toronto,Canada

Liu，Yanli,Iqbal，Aman,Li，Weiguo,et al. A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II[J]. Nature Communications,2022,13(1).

Liu，Yanli.,Iqbal，Aman.,Li，Weiguo.,Ni，Zuyao.,Wang，Yalong.,...&Min，Jinrong.(2022).A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.Nature Communications,13(1).

Liu，Yanli,et al."A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II".Nature Communications 13.1(2022).