小柯机器人

近日，西班牙巴塞罗那科学技术学院Ben Lehner及其团队绘制出蛋白质结合域的能量和异构图谱。相关论文于2022年4月6日发表在《自然》杂志上。

研究人员表示，蛋白质中远端位点之间的异构交流是生物调控的核心，但其表征仍然很差，这限制了对其的理解、工程和药物开发。这方面的一个重要原因是缺乏全面量化不同蛋白质中异构作用的方法。

研究人员解决了这一缺陷，并提出了一种使用深度突变扫描的方法，在全局范围内绘制异构体。该方法使用有效的实验设计，通过量化多种分子表型（检查结合力和蛋白质丰度），在多种遗传背景下，用神经网络拟合热力学模型，来集体推断了突变的因果生物物理效应。研究人员将该方法应用于人类最常见的两个蛋白质相互作用域，即SH3域和PDZ域，从而产生了全面的异构交流图谱。异构突变非常丰富，有一个很大的改变网络的"edgetic"变体的突变目标空间。突变更有可能在靠近结合界面、甘氨酸残基和连接到PDZ结构域内相反表面的特定残基上产生异生作用。这种对多种分子表型和多种遗传背景下的突变效应进行量化的一般方法，应该能够快速和全面地绘制出许多蛋白质的能量和异构图谱。

附：英文原文

Title: Mapping the energetic and allosteric landscapes of protein binding domains

Author: Faure, Andre J., Domingo, Jlia, Schmiedel, Jrn M., Hidalgo-Carcedo, Cristina, Diss, Guillaume, Lehner, Ben

Issue&Volume: 2022-04-06

Abstract: Allosteric communication between distant sites in proteins is central to biological regulation but still poorly characterized, limiting understanding, engineering and drug development1,2,3,4,5,6. An important reason for this is the lack of methods to comprehensively quantify allostery in diverse proteins. Here we address this shortcoming and present a method that uses deep mutational scanning to globally map allostery. The approach uses an efficient experimental design to infer en masse the causal biophysical effects of mutations by quantifying multiple molecular phenotypes—here we examine binding and protein abundance—in multiple genetic backgrounds and fitting thermodynamic models using neural networks. We apply the approach to two of the most common protein interaction domains found in humans, an SH3 domain and a PDZ domain, to produce comprehensive atlases of allosteric communication. Allosteric mutations are abundant, with a large mutational target space of network-altering ‘edgetic’ variants. Mutations are more likely to be allosteric closer to binding interfaces, at glycine residues and at specific residues connecting to an opposite surface within the PDZ domain. This general approach of quantifying mutational effects for multiple molecular phenotypes and in multiple genetic backgrounds should enable the energetic and allosteric landscapes of many proteins to be rapidly and comprehensively mapped.

DOI: 10.1038/s41586-022-04586-4

Source: https://www.nature.com/articles/s41586-022-04586-4

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