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

Yanli Liu (), Aman Iqbal, Weiguo Li, Zuyao Ni, Yalong Wang, Jurupula Ramprasad, Karan Joshua Abraham, Mengmeng Zhang, Dorothy Yanling Zhao, Su Qin, Peter Loppnau, Honglv Jiang, Xinghua Guo, Peter J. Brown, Xuechu Zhen, Guoqiang Xu, Karim Mekhail, Xingyue Ji, Mark T. Bedford, Jack F. Greenblatt and Jinrong Min ()
Additional contact information
Yanli Liu: Soochow University
Aman Iqbal: University of Toronto
Weiguo Li: Central China Normal University
Zuyao Ni: University of Toronto
Yalong Wang: The University of Texas MD Anderson Cancer Center
Jurupula Ramprasad: Soochow University
Karan Joshua Abraham: University of Toronto
Mengmeng Zhang: Soochow University
Dorothy Yanling Zhao: University of Toronto
Su Qin: University of Toronto
Peter Loppnau: University of Toronto
Honglv Jiang: Soochow University
Xinghua Guo: University of Toronto
Peter J. Brown: University of Toronto
Xuechu Zhen: Soochow University
Guoqiang Xu: Soochow University
Karim Mekhail: University of Toronto
Xingyue Ji: Soochow University
Mark T. Bedford: The University of Texas MD Anderson Cancer Center
Jack F. Greenblatt: University of Toronto
Jinrong Min: Central China Normal University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33229-5

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