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Publication Abstract from PubMed

We describe de novo-designed alpha-helical barrels (alphaHBs) that bind and discriminate between lipophilic biologically active molecules. alphaHBs have five or more alpha-helices arranged around central hydrophobic channels the diameters of which scale with oligomer state. We show that pentameric, hexameric, and heptameric alphaHBs 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 alphaHBs with submicromolar inhibitor constants; farnesol binds the hexamer and heptamer; but beta-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.

De Novo-Designed alpha-Helical Barrels as Receptors for Small Molecules.,Thomas F, Dawson WM, Lang EJM, Burton AJ, Bartlett GJ, Rhys GG, Mulholland AJ, Woolfson DN ACS Synth Biol. 2018 Jul 10. doi: 10.1021/acssynbio.8b00225. PMID:29944338^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.