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 A2A 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.