Diastereomeric Cyclopentane-Based Maltosides (CPMs) as Tools for Membrane Protein Study
2020
Das, Manabendra | Mahler, Florian | Hariharan, P. | Wang, Haoqing | Du, Yang | Mortensen, Jonas S. | Patallo, Eugenio Pérez | Ghani, Lubna | Gluck, David | Lee, Ho Jin | Byrne, Bernadette | Loland, Claus J. | Guan, Lan | Kobilka, Brian K. | Keller, Sandro | Chae, Pil Seok
Amphiphilic agents, called detergents, are invaluable tools for studying membrane proteins. However, membrane proteins encapsulated by conventional head-to-tail detergents tend to denature or aggregate, necessitating the development of structurally distinct molecules with improved efficacy. Here, a novel class of diastereomeric detergents with a cyclopentane core unit, designated cyclopentane-based maltosides (CPMs), were prepared and evaluated for their ability to solubilize and stabilize several model membrane proteins. A couple of CPMs displayed enhanced behavior compared with the benchmark conventional detergent, n-dodecyl-β-d-maltoside (DDM), for all the tested membrane proteins including two G-protein-coupled receptors (GPCRs). Furthermore, CPM-C12 was notable for its ability to confer enhanced membrane protein stability compared with the previously developed conformationally rigid NBMs [J. Am. Chem. Soc. 2017, 139, 3072] and LMNG. The effect of the individual CPMs on protein stability varied depending on both the detergent configuration (cis/trans) and alkyl chain length, allowing us draw conclusions on the detergent structure–property–efficacy relationship. Thus, this study not only provides novel detergent tools useful for membrane protein research but also reports on structural features of the detergents critical for detergent efficacy in stabilizing membrane proteins.
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