TY - JOUR
T1 - A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
AU - Liu, Yanli
AU - Iqbal, Aman
AU - Li, Weiguo
AU - Ni, Zuyao
AU - Wang, Yalong
AU - Ramprasad, Jurupula
AU - Abraham, Karan Joshua
AU - Zhang, Mengmeng
AU - Zhao, Dorothy Yanling
AU - Qin, Su
AU - Loppnau, Peter
AU - Jiang, Honglv
AU - Guo, Xinghua
AU - Brown, Peter J.
AU - Zhen, Xuechu
AU - Xu, Guoqiang
AU - Mekhail, Karim
AU - Ji, Xingyue
AU - Bedford, Mark T.
AU - Greenblatt, Jack F.
AU - Min, Jinrong
N1 - Funding Information:
We thank Dr. Wolfram Tempel for data collection and structure determination, Dr. John R. Walker for reviewing some of the crystal structures, and Dr. Dalia Barsyte-Lovejoy, Dr. Magdalena M Szewczyk and Dr. Hui Peng for technical assistance. This work was supported by the National Key R&D Program of China (2019YFA0802401, G.X.), the NSERC grant RGPIN-2021-02728 (J.M.), the National Natural Science Foundation of China (32271309, Y. L. and 81773608, X.J.), the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD), the CPRIT grant RP180804 (M.T.B.), and the NIH grant GM126421 (M.T.B.). The Structural Genomics Consortium is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, 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 and US), Pfizer and Takeda. Some diffraction experiments were performed at the Structural Biology Center and Northeastern Collaborative Access Team (NIGMS grant P30 GM124165) and Structural Biology Center beam lines at the Advanced Photon Source at Argonne National Laboratory. ANL is operated by the University of Chicago Argonne, LLC, for the U.S. Department of Energy Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Diffraction experiments described in this paper were also performed by using beamline 08ID-1 at the Canadian Light Source, which is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, the University of Saskatchewan, the Government of Saskatchewan, Western Economic Diversification Canada, the National Research Council Canada, and the Canadian Institutes of Health Research. The Mass Spectrometry Facility is supported in part by Cancer Prevention Research Institute of Texas (CPRIT) grant number RP190682.
Funding Information:
We thank Dr. Wolfram Tempel for data collection and structure determination, Dr. John R. Walker for reviewing some of the crystal structures, and Dr. Dalia Barsyte-Lovejoy, Dr. Magdalena M Szewczyk and Dr. Hui Peng for technical assistance. This work was supported by the National Key R&D Program of China (2019YFA0802401, G.X.), the NSERC grant RGPIN-2021-02728 (J.M.), the National Natural Science Foundation of China (32271309, Y. L. and 81773608, X.J.), the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD), the CPRIT grant RP180804 (M.T.B.), and the NIH grant GM126421 (M.T.B.). The Structural Genomics Consortium is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, 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 and US), Pfizer and Takeda. Some diffraction experiments were performed at the Structural Biology Center and Northeastern Collaborative Access Team (NIGMS grant P30 GM124165) and Structural Biology Center beam lines at the Advanced Photon Source at Argonne National Laboratory. ANL is operated by the University of Chicago Argonne, LLC, for the U.S. Department of Energy Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Diffraction experiments described in this paper were also performed by using beamline 08ID-1 at the Canadian Light Source, which is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, the University of Saskatchewan, the Government of Saskatchewan, Western Economic Diversification Canada, the National Research Council Canada, and the Canadian Institutes of Health Research. The Mass Spectrometry Facility is supported in part by Cancer Prevention Research Institute of Texas (CPRIT) grant number RP190682.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-33229-5
DO - 10.1038/s41467-022-33229-5
M3 - Article
C2 - 36114190
AN - SCOPUS:85138187363
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5453
ER -