David Baker团队的研究使用从头设计的蛋白质进行膜蛋白增溶和结构测定。2026年7月2日出版的《科学》杂志发表了这项成果。
该研究组描述了一种基于深度学习的通用设计方法，用于溶解天然膜蛋白，同时保留其序列、折叠、活性位点和配体结合特性。基因编码的新蛋白包裹在脂质相互作用的疏水表面，使它们具有耐热性和水溶性，不需要洗涤剂。该研究团队设计了用于单体和低聚β -桶外膜蛋白和螺旋多通跨膜蛋白的WRAP。一个2.95埃分辨率的冷冻电镜结构表明，WRAP可以用于溶液中膜蛋白的结构测定。作为开发梅毒疫苗的一个步骤，研究小组产生了梅毒螺旋体抗原的可溶性版本。
研究人员表示，整体膜蛋白广泛的疏水表面阻碍了其治疗方法和疫苗的开发，使其生产和结构分析变得复杂。
附：英文原文
Title: Membrane protein solubilization and structure determination using de novo–designed proteins
Author: Ljubica Mihaljevi, David E. Kim, Pooja D. Bandawane, Helen E. Eisenach, Andrew J. Borst, Alexis Courbet, Connor Weidle, Kenneth D. Carr, Everton Bettin, Qiushi Liu, Aldo T. Trejos, Sagardip Majumder, Surabhi Kokane, Alexander Stevens, Edin Muratspahi, Thomas Schlichthaerle, Marc Expòsit, Xinting Li, Mila Lamb, Analisa Nicole Azcárraga Murray, Rashmi Ravichandran, Elizabeth C. Williams, Shuyuan Hu, Lynda Stuart, Linda Grillová, Nicholas R. Thomson, Michael Landreh, Pengxiang Chang, Lorenzo Giacani, Melissa J. Caimano, Kelly L. Hawley, Neil P. King, David Baker
Issue&Volume: 2026-07-02
Abstract: Developing therapies and vaccines against integral membrane proteins is hindered by their extensive hydrophobic surfaces, which complicate production and structural analysis. Here, we describe a general deep learning–based design approach for solubilizing native membrane proteins while preserving their sequence, fold, active-site, and ligand-binding properties. Genetically encoded de novo protein WRAPs [water-soluble RFdiffused amphipathic proteins] surround the lipid-interacting hydrophobic surfaces, rendering them thermostable and water-soluble without the need for detergents. We design WRAPs for both monomeric and oligomeric beta-barrel outer membrane proteins and helical multipass transmembrane proteins. A 2.95-angstrom-resolution cryo–electron microscopy structure of WRAPed mycobacterial porin demonstrates that WRAPs can be used for the structural determination of membrane proteins in solution. As a step toward syphilis vaccine development, we generated soluble versions of Treponema pallidum antigens.
DOI: adr3817
Source: https://www.science.org/doi/10.1126/science.adr3817
期刊信息
Science：《科学》，创刊于1880年。隶属于美国科学促进会，最新IF：63.714
官方网址：https://www.sciencemag.org/
投稿链接：https://cts.sciencemag.org/scc/#/login