Cargando…

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

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 targ...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Yanli, Iqbal, Aman, Li, Weiguo, Ni, Zuyao, Wang, Yalong, Ramprasad, Jurupula, Abraham, Karan Joshua, Zhang, Mengmeng, Zhao, Dorothy Yanling, Qin, Su, Loppnau, Peter, Jiang, Honglv, Guo, Xinghua, Brown, Peter J., Zhen, Xuechu, Xu, Guoqiang, Mekhail, Karim, Ji, Xingyue, Bedford, Mark T., Greenblatt, Jack F., Min, Jinrong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481570/
https://www.ncbi.nlm.nih.gov/pubmed/36114190
http://dx.doi.org/10.1038/s41467-022-33229-5
_version_ 1784791298607153152
author Liu, Yanli
Iqbal, Aman
Li, Weiguo
Ni, Zuyao
Wang, Yalong
Ramprasad, Jurupula
Abraham, Karan Joshua
Zhang, Mengmeng
Zhao, Dorothy Yanling
Qin, Su
Loppnau, Peter
Jiang, Honglv
Guo, Xinghua
Brown, Peter J.
Zhen, Xuechu
Xu, Guoqiang
Mekhail, Karim
Ji, Xingyue
Bedford, Mark T.
Greenblatt, Jack F.
Min, Jinrong
author_facet Liu, Yanli
Iqbal, Aman
Li, Weiguo
Ni, Zuyao
Wang, Yalong
Ramprasad, Jurupula
Abraham, Karan Joshua
Zhang, Mengmeng
Zhao, Dorothy Yanling
Qin, Su
Loppnau, Peter
Jiang, Honglv
Guo, Xinghua
Brown, Peter J.
Zhen, Xuechu
Xu, Guoqiang
Mekhail, Karim
Ji, Xingyue
Bedford, Mark T.
Greenblatt, Jack F.
Min, Jinrong
author_sort Liu, Yanli
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9481570
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-94815702022-09-18 A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II Liu, Yanli Iqbal, Aman Li, Weiguo Ni, Zuyao Wang, Yalong Ramprasad, Jurupula Abraham, Karan Joshua Zhang, Mengmeng Zhao, Dorothy Yanling Qin, Su Loppnau, Peter Jiang, Honglv Guo, Xinghua Brown, Peter J. Zhen, Xuechu Xu, Guoqiang Mekhail, Karim Ji, Xingyue Bedford, Mark T. Greenblatt, Jack F. Min, Jinrong Nat Commun Article 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. Nature Publishing Group UK 2022-09-16 /pmc/articles/PMC9481570/ /pubmed/36114190 http://dx.doi.org/10.1038/s41467-022-33229-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Liu, Yanli
Iqbal, Aman
Li, Weiguo
Ni, Zuyao
Wang, Yalong
Ramprasad, Jurupula
Abraham, Karan Joshua
Zhang, Mengmeng
Zhao, Dorothy Yanling
Qin, Su
Loppnau, Peter
Jiang, Honglv
Guo, Xinghua
Brown, Peter J.
Zhen, Xuechu
Xu, Guoqiang
Mekhail, Karim
Ji, Xingyue
Bedford, Mark T.
Greenblatt, Jack F.
Min, Jinrong
A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
title A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
title_full A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
title_fullStr A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
title_full_unstemmed A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
title_short A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
title_sort small molecule antagonist of smn disrupts the interaction between smn and rnap ii
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481570/
https://www.ncbi.nlm.nih.gov/pubmed/36114190
http://dx.doi.org/10.1038/s41467-022-33229-5
work_keys_str_mv AT liuyanli asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT iqbalaman asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT liweiguo asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT nizuyao asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT wangyalong asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT ramprasadjurupula asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT abrahamkaranjoshua asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT zhangmengmeng asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT zhaodorothyyanling asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT qinsu asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT loppnaupeter asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT jianghonglv asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT guoxinghua asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT brownpeterj asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT zhenxuechu asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT xuguoqiang asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT mekhailkarim asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT jixingyue asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT bedfordmarkt asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT greenblattjackf asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT minjinrong asmallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT liuyanli smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT iqbalaman smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT liweiguo smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT nizuyao smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT wangyalong smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT ramprasadjurupula smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT abrahamkaranjoshua smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT zhangmengmeng smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT zhaodorothyyanling smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT qinsu smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT loppnaupeter smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT jianghonglv smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT guoxinghua smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT brownpeterj smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT zhenxuechu smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT xuguoqiang smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT mekhailkarim smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT jixingyue smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT bedfordmarkt smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT greenblattjackf smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii
AT minjinrong smallmoleculeantagonistofsmndisruptstheinteractionbetweensmnandrnapii