De Novo-Designed α-Helical Barrels as Receptors for Small Molecules

Franziska Thomas, Will Dawson, Eric Lang, Antony Burton, Gail Bartlett, Guto Rhys, Adrian Mulholland, Dek Woolfson*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

51 Citations (Scopus)
472 Downloads (Pure)


We describe de novo-designed α-helical barrels (αHBs) that bind and discriminate between lipophilic biologically active molecules. αHBs have five or more α-helices arranged around central hydrophobic channels the diameters of which scale with oligomer state. We show that pentameric, hexameric, and heptameric αHBs bind the environmentally sensitive dye 1,6-diphenylhexatriene (DPH) in the micromolar range and fluoresce. Displacement of the dye is used to report the binding of nonfluorescent molecules: palmitic acid and retinol bind to all three αHBs with submicromolar inhibitor constants; farnesol binds the hexamer and heptamer; but β-carotene binds only the heptamer. A co-crystal structure of the hexamer with farnesol reveals oriented binding in the center of the hydrophobic channel. Charged side chains engineered into the lumen of the heptamer facilitate binding of polar ligands: a glutamate variant binds a cationic variant of DPH, and introducing lysine allows binding of the biosynthetically important farnesol diphosphate.

Original languageEnglish
Pages (from-to)1808-1816
Number of pages9
JournalACS Synthetic Biology
Issue number7
Early online date30 Jun 2018
Publication statusPublished - 20 Jul 2018

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute
  • BCS and TECS CDTs


  • coiled coil
  • molecular dynamics
  • rational peptide design
  • small-molecule binding
  • α-helical barrel
  • Synthetic biology


Dive into the research topics of 'De Novo-Designed α-Helical Barrels as Receptors for Small Molecules'. Together they form a unique fingerprint.

Cite this