| Affiliation: | 1. Department of Bionanotechnology, Hanyang University, Ansan, 15588 Korea Current address: Department of Chemistry, Mirpur University of Science & Technology, Mirpur, AJK, 10250 Pakistan).;2. Molecular and Cellular Physiology, Stanford, CA, 94305 USA;3. Department of Neuroscience, University of Copenhagen, 2200 Copenhagen, Denmark;4. Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, School of Medicine, Texas Tech University Health Sciences Center Lubbock, TX, 79430 USA;5. Molecular and Cellular Physiology and Structural Biology, Stanford University, Stanford, CA, 94305 USA;6. Department of Bionanotechnology, Hanyang University, Ansan, 15588 Korea;7. Molecular Biophysics, Technische Universität Kaiserslautern (TUK), Erwin-Schrödinger-Str. 13, 67663 Kaiserslautern, Germany;8. Department of Life Sciences, Imperial College London, London, SW7 2AZ UK |
| Abstract: | Amphipathic agents are widely used in various fields including biomedical sciences. Micelle-forming detergents are particularly useful for in vitro membrane-protein characterization. As many conventional detergents are limited in their ability to stabilize membrane proteins, it is necessary to develop novel detergents to facilitate membrane-protein research. In the current study, we developed novel trimaltoside detergents with an alkyl pendant-bearing terphenyl unit as a hydrophobic group, designated terphenyl-cored maltosides (TPMs). We found that the geometry of the detergent hydrophobic group substantially impacts detergent self-assembly behavior, as well as detergent efficacy for membrane-protein stabilization. TPM-Vs, with a bent terphenyl group, were superior to the linear counterparts (TPM-Ls) at stabilizing multiple membrane proteins. The favorable protein stabilization efficacy of these bent TPMs is likely associated with a binding mode with membrane proteins distinct from conventional detergents and facial amphiphiles. When compared to n-dodecyl-β-d -maltoside (DDM), most TPMs were superior or comparable to this gold standard detergent at stabilizing membrane proteins. Notably, TPM-L3 was particularly effective at stabilizing the human β2 adrenergic receptor (β2AR), a G-protein coupled receptor, and its complex with Gs protein. Thus, the current study not only provides novel detergent tools that are useful for membrane-protein study, but also suggests a critical role for detergent hydrophobic group geometry in governing detergent efficacy. |
