Nat. Commun：DMDA-PatA通过将eIF4A和DDX3锚定到GNG基序上介导RNA序列选择性翻译抑制-动脉网

Nat. Commun：DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs

Nature 等信源发布 2024-09-02 18:51

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AbstractSmall-molecule compounds that elicit mRNA-selective translation repression have attracted interest due to their potential for expansion of druggable space. However, only a limited number of examples have been reported to date. Here, we show that desmethyl desamino pateamine A (DMDA-PatA) represses translation in an mRNA-selective manner by clamping eIF4A, a DEAD-box RNA-binding protein, onto GNG motifs.

摘要引起mRNA选择性翻译抑制的小分子化合物由于其扩展药物空间的潜力而引起了人们的兴趣。然而，迄今为止，仅报告了有限数量的例子。在这里，我们显示去甲基脱氨基-patamine A（DMDA-PatA）通过将死盒RNA结合蛋白eIF4A夹在GNG基序上以mRNA选择性方式抑制翻译。

By systematically comparing multiple eIF4A inhibitors by ribosome profiling, we found that DMDA-PatA has unique mRNA selectivity for translation repression. Unbiased Bind-n-Seq reveals that DMDA-PatA-targeted eIF4A exhibits a preference for GNG motifs in an ATP-independent manner. This unusual RNA binding sterically hinders scanning by 40S ribosomes.

通过核糖体分析系统地比较多种eIF4A抑制剂，我们发现DMDA-PatA对翻译抑制具有独特的mRNA选择性。无偏的Bind-n-Seq揭示了DMDA-PatA靶向的eIF4A以不依赖ATP的方式表现出对GNG基序的偏好。这种不寻常的RNA结合在空间上阻碍了40S核糖体的扫描。

A combination of classical molecular dynamics simulations and quantum chemical calculations, and the subsequent development of an inactive DMDA-PatA derivative reveals that the positive charge of the tertiary amine on the trienyl arm induces G selectivity. Moreover, we identified that DDX3, another DEAD-box protein, is an alternative DMDA-PatA target with the same effects on eIF4A.

经典分子动力学模拟和量子化学计算的结合，以及随后开发的无活性DMDA-PatA衍生物表明，三烯臂上叔胺的正电荷诱导了G选择性。此外，我们发现另一种DEAD盒蛋白DDX3是一种替代的DMDA PatA靶标，对eIF4A具有相同的作用。

Our results provide an example of the sequence-selective anchoring of RNA-binding proteins and the mRNA-selective inhibition of protein synthesis by small-molecule compounds..

我们的研究结果为RNA结合蛋白的序列选择性锚定和小分子化合物对蛋白质合成的mRNA选择性抑制提供了一个例子。。

IntroductionThe production of harmful proteins often leads to deleterious outcomes in cells, causing a wide variety of diseases. Due to the limited druggable proteome1, compounds that modulate the synthesis of unwelcome proteins at the translational level provide attractive therapeutic opportunities2.

引言有害蛋白质的产生通常会导致细胞中的有害结果，导致多种疾病。由于有限的可药用蛋白质组1，在翻译水平上调节不受欢迎蛋白质合成的化合物提供了有吸引力的治疗机会2。

Although several compounds that suppress translation in an mRNA-selective manner have been identified2,3, the number of such compounds is still limited, warranting further identification of a new class with such activity.Repurposing natural secondary metabolites for pharmacological use has been a common strategy in drug development4.

尽管已经鉴定出几种以mRNA选择性方式抑制翻译的化合物2,3，但这些化合物的数量仍然有限，需要进一步鉴定具有这种活性的新类别。将天然次生代谢物重新用于药理用途一直是药物开发中的常见策略4。

Indeed, translation inhibitors are not exceptions, as a variety of antibiotics targeting ribosomes have been exploited5. In addition to ribosomes, eukaryotic translation initiation factor (eIF) 4 A has been found to be a common target of a variety of natural products, presenting a vulnerability in cancer6.

事实上，翻译抑制剂也不例外，因为已经开发了多种靶向核糖体的抗生素5。除核糖体外，真核翻译起始因子（eIF）4A已被发现是多种天然产物的共同靶标，在癌症中具有脆弱性6。

These compounds include hippuristanol (Hipp) from a soft coral (Isis hippuris)7,8,9,10,11, rocaglates from plants of the Aglaia genus12,13,14,15,16,17,18,19,20, pateamine A (PatA) from a sponge (Mycale sp.) or its microbiome symbionts21,22,23,24,25,26,27,28,29,30,31,32, and sanguinarine (San) from poppy plants (Macleaya cordata and Argemone Mexicana)33,34.eIF4A is an ATP-dependent DEAD-box type RNA-binding protein that forms a complex with the cap-binding protein eIF4E and scaffold protein eIF4G and then facilitates the loading of the 43S preinitiation complex onto the 5′ ends of mRNA and subsequent scanning of the 5′ untranslated region (UTR)35,36.

这些化合物包括来自软珊瑚（Isis hippuris）7,8,9,10,11的马匹甾醇（Hipp），来自Aglaia属植物12,13,14,15,16,17,18,19,20的罗卡糖，来自海绵（Mycale sp.）或其微生物群共生体21,22,23,24,25,26,27,28,29,30,31,32的patamine a（PatA），以及来自罂粟植物（Macleaya cordata和Argemone Mexicana）的血根碱（San）33,34.eIF4A是一种依赖ATP的死盒型RNA结合蛋白，与帽结合蛋白eIF4E和支架蛋白eIF4G形成复合物，然后促进43S预起始复合物加载到mRNA的5'端，随后扫描5'非翻译区（UTR）35,36。

In mammals, this protein is encoded by two genes, EIF4A1 and EIF4A2. Hipp and San have been shown to reduce the RNA-binding ability of eIF4A8,9,10,34, simply inactivating the function of eIF4A in.

在哺乳动物中，这种蛋白质由两个基因EIF4A1和EIF4A2编码。Hipp和San已被证明可以降低eIF4A8,9,10,34的RNA结合能力，从而简单地使eIF4A的功能失活。

Data availability

数据可用性

The data supporting the findings of this study are available from the corresponding authors upon request. The results of ribosome profiling, RNA pulldown-Seq, and RNA Bind-n-Seq (GEO: GSE243312) obtained in this study have been deposited in the National Center for Biotechnology Information (NCBI) database.

支持本研究结果的数据可应要求从通讯作者处获得。本研究中获得的核糖体分析，RNA pulldown-Seq和RNA Bind-n-Seq（GEO:GSE243312）的结果已保存在国家生物技术信息中心（NCBI）数据库中。

All the input and result files for the FMO calculations are available at the FMODB [https://drugdesign.riken.jp/FMODB/detail.php?FMODBID = “ID in the list”]106 (see Supplementary Table 1 for the ID list). Source data are provided with this paper..

FMODB提供了FMO计算的所有输入和结果文件[https://drugdesign.riken.jp/FMODB/detail.php?FMODBID = “列表中的ID”]106（ID列表见补充表1）。本文提供了源数据。。

Code availability

代码可用性

For the data analysis for ribosome profiling, RNA pulldown-Seq, and RNA Bind-n-Seq, we deposited key codes in Zenodo (https://doi.org/10.5281/zenodo.11064746)107, which used reported custom script (https://github.com/ingolia-lab/RiboSeq). For the MD and FMO calculations, we used the abmptools on GitHub (https://github.com/kojioku/abmptools)..

为了对核糖体分析、RNA pulldown-Seq和RNA Bind-n-Seq进行数据分析，我们在Zenodo中保存了关键代码(https://doi.org/10.5281/zenodo.11064746)(https://github.com/ingolia-lab/RiboSeq)。对于MD和FMO计算，我们使用了GitHub上的abmptools(https://github.com/kojioku/abmptools)。。

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Saito，H。DMDA PatA的自定义脚本通过将eIF4A和DDX3锚定到GNG基序来介导RNA序列选择性翻译抑制。。https://doi.org/10.5281/zenodo.11064746（2024年）。下载参考文献致谢我们感谢岩崎实验室所有成员的建设性讨论和技术帮助。

We are grateful to Dr. K. Dodo, Dr. K. Okuwaki, Dr. K. Kato, Dr. C. Watanabe, and Dr. T. Honma for their helpful advice. Hipp was a kind gift from Dr. J. Tanaka. San was a kind gift from Dr. J. Liu. We thank Dr. C.-X. Zhuo and S. Schulthoff for preparing the pateamine derivatives and C. Wirtz for excellent NMR support (and all at the MPI Mülheim).

我们感谢K.Dodo博士，K.Okuwaki博士，K.Kato博士，C.Watanabe博士和T.Honma博士的有益建议。希普是田中博士的礼物。San是J.Liu博士的礼物。我们感谢C.-X.Zhuo博士和S.Schulthoff博士制备了patamine衍生物，感谢C.Wirtz出色的NMR支持（以及所有在MPI Mülheim的支持）。

We are grateful to Dr. N.T. Ingolia for sharing the plasmids. This study used facilities of the HOKUSAI SailingShip supercomputer facility at RIKEN; Sanger sequencing at the Support Unit for Bio-Material Analysis, RIKEN CBS Research Resources Division; and deep sequencing via HiSeq 4000, supported by the National Institutes for Health (NIH) Instrumentation Grant (S10 OD018174), in QB3 Genomics, UC Berkeley, Berkeley, CA, (RRID:SCR_022170).

我们感谢N.T.Ingolia博士分享质粒。这项研究使用了位于里肯的HOKUSAI SailingShip超级计算机设施；RIKEN CBS研究资源部生物材料分析支持部门的Sanger测序；。

MD simulations and FMO calculations were performed using the Fugaku supercomputer (project ID: hp220143) and the TSUBAME 3.0 supercomputer (Tokyo Institute of Technology, Japan). This work was supported by the Japan Society for the Promotion of Science (JSPS) (JP23H02415 and JP23H00095 to S.I.; JP23H05473 to M.Y.; JP23K05648 to Y.S.), the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (JP20H05784 and JP24H02307 to S.I.; JP21H05281 to T.I.; JP21H05734 and JP23H04268 to Y.S.; JP23H04882 to M.Y.), the Japan Agency for Medical Research and Development (AMED) (JP23gm1410001 to S.I.

使用Fugaku超级计算机（项目编号：hp220143）和TSUBAME 3.0超级计算机（日本东京理工学院）进行MD模拟和FMO计算。这项工作得到了日本科学促进会（JSPS）的支持（JP23H02415和JP23H00095至S.I.；JP23H05473至M.Y.；JP23K05648至Y.S.），教育、文化、体育、科学和技术部（MEXT）（JP20H05784和JP24H02307至S.I.；JP21H05281至T.I.；JP21H05734和JP23H04268至Y.S.；JP23H04882至M.Y.），日本医学研究与发展署（AMED）（JP23gm1410001至S.I。

and T.I.), and RIKEN (Pioneering Projects “Biology of In.

和T.I.）和RIKEN（开创性项目“In的生物学”。

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PubMed Google ScholarContributionsConceptualization: H.S. and S.I.; Methodology: H.S., Y.H., M.C., T.S.-P., Y.S., M.T., and A.F.; Formal analysis: H.S., Y.H., M.C., Y.S., M.T., and A.F.; Investigation: H.S., H.S., Y.H., M.C., Y.S., M.T., and A.F.; Resources: D.R. and A.F.; Writing – Original Draft: S.I.; Writing – Review & Editing: H.S., Y.H., M.C., T.S.-P., Y.S., M.T., D.R., M.Y., A.F., T.I., K.F., and S.I.; Visualization: H.S.

PubMed谷歌学术贡献概念：H.S.和S.I。；方法学：H.S.，Y.H.，M.C.，T.S.-P.，Y.S.，M.T。和A.F。；形式分析：H.S.，Y.H.，M.C.，Y.S.，M.T。和A.F。；。；资源：D.R.和A.F。；写作-原稿：S.I。；写作-评论和编辑：H.S.，Y.H.，M.C.，T.S.-P.，Y.S.，M.T.，D.R.，M.Y.，A.F.，T.I.，K.F。和S.I。；可视化：H.S。

and S.I.; Supervision: Y.S., M.Y., A.F., T.I., K.F., and S.I.; Project administration: S.I.; and Funding Acquisition: T.S.-P., Y.S., D.R., M.Y., T.I., and S.I.Corresponding authorCorrespondence to.

和S.I。；监督：Y.S.，M.Y.，A.F.，T.I.，K.F。和S.I。；项目管理：S.I。；和资金获取：T.S.-P.，Y.S.，D.R.，M。Y、，T.I.和S.I.对应作者对应。

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Reprints and permissionsAbout this articleCite this articleSaito, H., Handa, Y., Chen, M. et al. DMDA-PatA mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs.

转载和许可本文引用本文Saito，H.，Handa，Y.，Chen，M。等人。DMDA PatA通过将eIF4A和DDX3锚定到GNG基序来介导RNA序列选择性翻译抑制。

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