TY - JOUR

T1 - Foldable detergents for membrane protein study

T2 - Importance of detergent core flexibility in protein stabilization

AU - Ghani, Lubna

AU - Kim, Seonghoon

AU - Wang, Haoqing

AU - Lee, Hyun Sung

AU - Mortensen, Jonas S

AU - Katsube, Satoshi

AU - Du, Yang

AU - Sadaf, Aiman

AU - Byrne, Bernadette

AU - Guan, Lan

AU - Loland, Claus J

AU - Kobilka, Brian K

AU - Im, Wonpil

AU - Chae, Pil Seok

AU - Ahmed, Waqar

N1 - © 2022 Wiley-VCH GmbH.

PY - 2022

Y1 - 2022

N2 - Membrane proteins are of biological and pharmaceutical significance. However, their structural study is extremely challenging mainly due to the fact that only a small number of chemical tools is suitable for stabilizing membrane proteins in solution. Detergents are widely used in membrane protein study, but conventional detergents are generally poor at stabilizing challenging membrane proteins such as G protein-coupled receptors and protein complexes. In the current study, we prepared tandem triazine-based maltosides (TZMs) with two amphiphilic triazine units connected by different diamine linkers, hydrazine (TZM-Hs) and 1,2-ethylenediamine (TZM-Es). These TZMs were consistently superior to a gold standard detergent (DDM) in terms of stabilizing a few membrane proteins. In addition, the TZM-Es containing a long linker showed more general protein stabilization efficacy with multiple membrane proteins than the TZM-Hs containing a short linker. This result indicates that introduction of the flexible1,2-ethylenediamine linker between two rigid triazine rings enables the TZM-Es to fold into favourable conformations in order to promote membrane protein stability. The novel concept of detergent foldability introduced in the current study has potential use for rational detergent design and membrane protein applications.

AB - Membrane proteins are of biological and pharmaceutical significance. However, their structural study is extremely challenging mainly due to the fact that only a small number of chemical tools is suitable for stabilizing membrane proteins in solution. Detergents are widely used in membrane protein study, but conventional detergents are generally poor at stabilizing challenging membrane proteins such as G protein-coupled receptors and protein complexes. In the current study, we prepared tandem triazine-based maltosides (TZMs) with two amphiphilic triazine units connected by different diamine linkers, hydrazine (TZM-Hs) and 1,2-ethylenediamine (TZM-Es). These TZMs were consistently superior to a gold standard detergent (DDM) in terms of stabilizing a few membrane proteins. In addition, the TZM-Es containing a long linker showed more general protein stabilization efficacy with multiple membrane proteins than the TZM-Hs containing a short linker. This result indicates that introduction of the flexible1,2-ethylenediamine linker between two rigid triazine rings enables the TZM-Es to fold into favourable conformations in order to promote membrane protein stability. The novel concept of detergent foldability introduced in the current study has potential use for rational detergent design and membrane protein applications.

U2 - 10.1002/chem.202200116

DO - 10.1002/chem.202200116

M3 - Journal article

C2 - 35238091

VL - 28

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

SN - 0947-6539

IS - 21

M1 - e202200116

ER -