德国乔治-奥古斯都-哥廷根大学的Kai Tittmann和Ricardo A. Mata等研究人员合作报道了酶协同性中的低势垒氢键。2019年9月18日，国际知名学术期刊《自然》在线发表了这一成果。
研究人员在实验中观察到波动的低势垒氢键作为多聚酶协同作用途径中的转换元件。研究人员在两种多聚酶的超高分辨率X射线晶体结构中观察到这些低势垒氢键，并且已经使用算法验证了它们的分配。活性位点的催化事件在由酸性侧链和水分子组成的回路中的低势垒氢键和普通氢键之间切换，并通过表现为原子牛顿摆质子的集体重新定位传递信号。由此产生的通信使寡聚物中的催化同步。
这项研究为存在于蛋白质中且还与酶协同性有关的低势垒氢键，提供了几个证据和工作模型。该发现提出了药物和酶设计的新原理，其中可以有目的地利用残基序列来实现远程通信并因此调节工程化生物分子。
研究人员表示，人们对许多蛋白质协同和变构调节的潜在分子机制有很好的理解，血红蛋白和天冬氨酸转氨甲酰酶就是原型实例。效应子的结合通常导致蛋白质的结构转变，这通过信号传导途径传播到远程位点，并且涉及三级、有时甚至是四级水平的显著变化。然而，这些信号的起源和原子水平上远程信号传导的分子机制仍不清楚。信号通路中不同的空间尺度和时间尺度使实验观察具有挑战性，特别是现有的结构分析方法无法显示移动质子的位置和运动。
附：英文原文
Title: Low-barrier hydrogen bonds in enzyme cooperativity
Author: Shaobo Dai, Lisa-Marie Funk, Fabian Rabe von Pappenheim, Viktor Sautner, Mirko Paulikat, Benjamin Schrder, Jon Uranga, Ricardo A. Mata, Kai Tittmann
Issue&Volume: 2019-09-18
Abstract:
The underlying molecular mechanisms of cooperativity and allosteric regulation are well understood for many proteins, with haemoglobin and aspartate transcarbamoylase serving as prototypical examples1,2. The binding of effectors typically causes a structural transition of the protein that is propagated through signalling pathways to remote sites and involves marked changes on the tertiary and sometimes even the quaternary level1,2,3,4,5. However, the origin of these signals and the molecular mechanism of long-range signalling at an atomic level remain unclear5,6,7,8. The different spatial scales and timescales in signalling pathways render experimental observation challenging; in particular, the positions and movement of mobile protons cannot be visualized by current methods of structural analysis. Here we report the experimental observation of fluctuating low-barrier hydrogen bonds as switching elements in cooperativity pathways of multimeric enzymes. We have observed these low-barrier hydrogen bonds in ultra-high-resolution X-ray crystallographic structures of two multimeric enzymes, and have validated their assignment using computational calculations. Catalytic events at the active sites switch between low-barrier hydrogen bonds and ordinary hydrogen bonds in a circuit that consists of acidic side chains and water molecules, transmitting a signal through the collective repositioning of protons by behaving as an atomistic Newton’s cradle. The resulting communication synchronizes catalysis in the oligomer. Our studies provide several lines of evidence and a working model for not only the existence of low-barrier hydrogen bonds in proteins, but also a connection to enzyme cooperativity. This finding suggests new principles of drug and enzyme design, in which sequences of residues can be purposefully included to enable long-range communication and thus the regulation of engineered biomolecules.
DOI: 10.1038/s41586-019-1581-9
Source:https://www.nature.com/articles/s41586-019-1581-9
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
