title: Crystal structures of human transthyretin complexed with glabridin.
abstract: Transthyretin (TTR) is a plasma protein implicated in human amyloid diseases. Several small molecules that bind to the thyroxine-binding site of TTR have been shown to stabilize the TTR tetramer and to inhibit amyloid fibril formation of TTR. Herein, we demonstrated that glabridin (Glab), a prenylated isoflavan isolated from Glycyrrhiza glabra L., inhibited aggregation of TTR in a thioflavin assay. The TTR-Glab complex structure revealed a novel binding mode including a CH-π interaction with A108 and a hydrogen bond with K15. A structural comparison with the wild type-apo structure revealed that the CH-π interaction with A108 was strengthened by the induced-fit conformational change upon Glab binding. Furthermore, the binding of Glab induced a rotation of the T119 side chain, and the inclusion of a water molecule, leading to stabilization of the dimer-dimer interface. These results demonstrate that Glab is a novel inhibitor of TTR fibrillization and suggest the molecular mechanism by which Glab binding stabilizes the tetramer.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Yuto
authors.initials: Y
authors.lastname: Kosaka
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
mesh_terms: D000682:Amyloid / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007529:Isoflavones / Q000737:chemistry*; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry*; D011228:Prealbumin / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D000682:Amyloid; D007529:Isoflavones; D010636:Phenols; D011228:Prealbumin; C107601:glabridin