Journal Article

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

Loppnau, Peter, Qin, Su, Bedford, Mark T., Li, Weiguo, Iqbal, Aman, Mekhail, Karim, Zhang, Mengmeng, Guo, Xinghua, Abraham, Karan Joshua, Min, Jinrong, Ni, Zuyao, Zhen, Xuechu, Xu, Guoqiang, Zhao, Dorothy Yanling, Brown, Peter J., Greenblatt, Jack F., Ramprasad, Jurupula, Wang, Yalong, Jiang, Honglv, Liu, Yanli, Ji, Xingyue

2022

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/47 / 140/58 / 49/98 / 631/337/458/1648 / 631/337/572 / 631/535/1266 / 631/92/613 / 82/80 / Antagonists / Antisense RNA / Aromatic compounds / Atrophy / CRISPR / Depletion / DNA-directed RNA polymerase / Humanities and Social Sciences / Humans / Motor Neurons - metabolism / multidisciplinary / Muscular Atrophy, Spinal - metabolism / Mutagenesis / Neuromuscular diseases / Proteins / RNA polymerase / RNA polymerase II / RNA Polymerase II - drug effects / RNA Polymerase II - metabolism / RNA-mediated interference / Science / Science (multidisciplinary) / Selective binding / SMN Complex Proteins - antagonists & inhibitors / SMN Complex Proteins - drug effects / SMN Complex Proteins - metabolism / SMN protein / Spinal muscular atrophy / Transcription termination