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修复酶AlkB对底物进行识别的结构基础。

Structural basis for substrate discrimination by repair enzyme, AlkB.

作者信息

Jayanth Namrata, Ogirala Nirmala, Yadav Anil, Puranik Mrinalini

机构信息

National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK Campus Bellary Road Bangalore 560065 India

Indian Institute of Science Education and Research (IISER) Pune Maharashtra 411008 India.

出版信息

RSC Adv. 2018 Jan 3;8(3):1281-1291. doi: 10.1039/c7ra11333a. eCollection 2018 Jan 2.

DOI:10.1039/c7ra11333a
PMID:35540905
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9076979/
Abstract

AlkB, a repair enzyme of the dioxygenase family, catalyses the removal of mutagenic methylated nucleotides from the genome. Known for substrate promiscuity, AlkB's catalytic mechanism and conformational changes accompanying substrate binding have been extensively dissected. However, the structural parameters of various substrates governing their recognition by AlkB still remain elusive. In this work, through solution-state vibrational spectra of methylated substrates bound to AlkB in combination with computational analysis, we show that the recognition specificity is dictated by the protonation states of the substrates. Specificity is conferred predominantly through hydrogen bonding and cation-π interactions. Furthermore, we report on the interaction of AlkB with normal, unmodified nucleotides, wherein the presence of an exocyclic amino group serves as an essential criterion for the initial process of substrate recognition. Taken together, these results provide a rationale for structural determinants of substrate specificity as well as mode of lesion discrimination employed by AlkB.

摘要

AlkB是双加氧酶家族的一种修复酶，可催化从基因组中去除诱变的甲基化核苷酸。AlkB以底物混杂性而闻名，其催化机制以及伴随底物结合的构象变化已被广泛剖析。然而，决定AlkB对各种底物识别的结构参数仍然不清楚。在这项工作中，通过结合计算分析的与AlkB结合的甲基化底物的溶液态振动光谱，我们表明识别特异性由底物的质子化状态决定。特异性主要通过氢键和阳离子-π相互作用赋予。此外，我们报告了AlkB与正常的、未修饰的核苷酸的相互作用，其中环外氨基的存在是底物识别初始过程的一个基本标准。综上所述，这些结果为底物特异性的结构决定因素以及AlkB采用的损伤区分模式提供了理论依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/fe9aedc178e0/c7ra11333a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/62aeb558fc6e/c7ra11333a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/a71792ea0474/c7ra11333a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/a0b7ee4bd4fd/c7ra11333a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/4c9e2ee6e3cd/c7ra11333a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/20bb55487d52/c7ra11333a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/fe9aedc178e0/c7ra11333a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/62aeb558fc6e/c7ra11333a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/a71792ea0474/c7ra11333a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/a0b7ee4bd4fd/c7ra11333a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/4c9e2ee6e3cd/c7ra11333a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/20bb55487d52/c7ra11333a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a44/9076979/fe9aedc178e0/c7ra11333a-f6.jpg

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本文引用的文献

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UV resonance Raman study of cation-π interactions in an indole crown ether.吲哚冠醚中阳离子-π相互作用的紫外共振拉曼光谱研究
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Switching demethylation activities between AlkB family RNA/DNA demethylases through exchange of active-site residues.通过交换活性位点残基在 AlkB 家族 RNA/DNA 去甲基酶之间切换去甲基化活性。
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振动能量分布分析（VEDA）：范围和局限性。
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AlkB dioxygenase preferentially repairs protonated substrates: specificity against exocyclic adducts and molecular mechanism of action.AlkB 双氧酶优先修复质子化的底物：针对环外加合物的特异性和作用机制。
J Biol Chem. 2013 Jan 4;288(1):432-41. doi: 10.1074/jbc.M112.353342. Epub 2012 Nov 12.
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