4N87

Crystal structures of human transthyretin complexed with glabridin

(2014) J Med Chem 57: 1090-1096

• PubMed: 24422526 Search on PubMed
• DOI: https://doi.org/10.1021/jm401832j
• Primary Citation of Related Structures:  
  4N85, 4N86, 4N87


• PubMed 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.

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Organizational Affiliation: 

Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.