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Self-assembly behavior and application of terphenyl-cored trimaltosides for membrane-protein studies: impact of detergent hydrophobic group geometry on protein stability

  • Ehsan, M
  • Du, Y
  • Mortensen, JS
  • Hariharan, P
  • Qu, Q
  • Ghani, L
  • Das, M
  • Grethen, A
  • Byrne, B
  • Skiniotis, G
  • Keller, S
  • Loland, CJ
  • Guan, L
  • Kobilka, BK
  • Chae, PS
Publication Date
Jun 01, 2019
Spiral - Imperial College Digital Repository
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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 (β2 AR), 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.

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