National Center for
4Y9E: Crystal Structure Of V30m Mutated Transthyretin In Complex With Gamma- Mangostin
Sci Rep (2015) 5 p.13570
Transthyretin (TTR) is a homotetrameric protein involved in human hereditary amyloidoses. The discovery and development of small molecules that inhibit the amyloid fibril formation of TTR is one of the therapeutic strategies for these diseases. Herein, we discovered that gamma-mangostin (gamma-M) is an effective inhibitor against the amyloid fibril formation of V30M amyloidogenic TTR. In-vitro binding assays revealed that gamma-M was the most potent of the selected xanthone derivatives, and it bound to the thyroxine (T4)-binding sites and stabilized the TTR tetramer. X-ray crystallographic analysis revealed the diagonal binding mode of gamma-M and the two binding sites of chloride ions at the T4-binding site. One of the chloride ions was replaced with a water molecule in the alpha-mangostin complex, which is a methylated derivative of gamma-M. The stronger inhibitory potency of gamma-M could be explained by the additional hydrogen bonds with the chloride ion. The present study establishes gamma-M as a novel inhibitor of TTR fibrillization.