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潮霉素A核糖体结合位点的晶体学表征及其作用分子机制

Crystallographic characterization of the ribosomal binding site and molecular mechanism of action of Hygromycin A.

作者信息

Kaminishi Tatsuya, Schedlbauer Andreas, Fabbretti Attilio, Brandi Letizia, Ochoa-Lizarralde Borja, He Cheng-Guang, Milón Pohl, Connell Sean R, Gualerzi Claudio O, Fucini Paola

机构信息

Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Bizkaia, Spain.

Laboratory of Genetics, Department of Biosciences and Veterinary Medicine, University of Camerino, 62032 Camerino, Italy.

出版信息

Nucleic Acids Res. 2015 Nov 16;43(20):10015-25. doi: 10.1093/nar/gkv975. Epub 2015 Oct 12.

DOI:10.1093/nar/gkv975
PMID:26464437
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4787777/
Abstract

Hygromycin A (HygA) binds to the large ribosomal subunit and inhibits its peptidyl transferase (PT) activity. The presented structural and biochemical data indicate that HygA does not interfere with the initial binding of aminoacyl-tRNA to the A site, but prevents its subsequent adjustment such that it fails to act as a substrate in the PT reaction. Structurally we demonstrate that HygA binds within the peptidyl transferase center (PTC) and induces a unique conformation. Specifically in its ribosomal binding site HygA would overlap and clash with aminoacyl-A76 ribose moiety and, therefore, its primary mode of action involves sterically restricting access of the incoming aminoacyl-tRNA to the PTC.

摘要

潮霉素A（HygA）与核糖体大亚基结合并抑制其肽基转移酶（PT）活性。所呈现的结构和生化数据表明，HygA不会干扰氨酰基-tRNA与A位点的初始结合，但会阻止其随后的调整，使其无法在PT反应中作为底物发挥作用。在结构上，我们证明HygA结合在肽基转移酶中心（PTC）内并诱导出独特的构象。具体而言，在其核糖体结合位点，HygA会与氨酰基-A76核糖部分重叠并发生冲突，因此，其主要作用方式是在空间上限制进入的氨酰基-tRNA进入PTC。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/66d11b83f63f/gkv975fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/6c3c9196a1b4/gkv975fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/cae4f9a3d439/gkv975fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/fc7960ae8dae/gkv975fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/c657e9fd23b4/gkv975fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/d4d5c43c7c0d/gkv975fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/66d11b83f63f/gkv975fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/6c3c9196a1b4/gkv975fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/cae4f9a3d439/gkv975fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/fc7960ae8dae/gkv975fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/c657e9fd23b4/gkv975fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/d4d5c43c7c0d/gkv975fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fd1/4787777/66d11b83f63f/gkv975fig6.jpg

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2
A proton wire to couple aminoacyl-tRNA accommodation and peptide-bond formation on the ribosome.质子导线连接核糖体上氨酰基-tRNA 的容纳和肽键的形成。
Nat Struct Mol Biol. 2014 Sep;21(9):787-93. doi: 10.1038/nsmb.2871. Epub 2014 Aug 17.
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Total synthesis of nucleoside antibiotic A201A.
端核糖体 RNA 螺旋之间的相互作用稳定了大亚基。
RNA. 2023 Oct;29(10):1500-1508. doi: 10.1261/rna.079690.123. Epub 2023 Jul 7.
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Antibiotic synergist OM19r reverses aminoglycoside resistance in multidrug-resistant .抗生素增效剂OM19r可逆转多重耐药菌对氨基糖苷类药物的耐药性。
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