Two-Dimensional Detergent Expansion Strategy for Membrane Protein Studies

Detergents are the most frequently applied reagents in membrane protein (MP) studies. The limited diversity of one-head-one-tailed traditional detergents, however, is far from sufficient for structurally distinct MPs. Expansion of detergent repertoire has a continuous momentum. In line with the speculation that detergent pre-assembly exerts superiority, herein we report for the first time cross-conjugation of two series of monomeric detergents for constructing a two-dimensional library of dimeric detergents. Optimum detergents stood out with unique preferences in the systematic evaluation of individual MPs. Furthermore, unprecedented hybrid detergents 14M8G and 14M9G enabled high-quality EM study of transporter MsbA and NMR study of G protein-coupled receptor A(2A)AR, respectively. Given the abundance of cross-coupling chemistries, comprehensive diversity could be readily covered that would facilitate the finding of new detergents for the manipulation of thorny MPs and innovation of the functional and structural study in future.

Automated summary

Detergents are commonly used in membrane protein studies, but the limited diversity of traditional detergents restricts their applications to structurally distinct proteins. In this study, the authors report the cross-conjugation of two series of monomeric detergents to construct a library of dimeric detergents for a wider range of applications. Optimum detergents were identified through systematic evaluation and hybrid detergents enabled high-quality studies of different proteins. The findings suggest that the use of cross-coupling chemistries can greatly expand the diversity of detergents for future studies on membrane proteins.