4Y9F

Crystal structure of V30M mutated transthyretin with bromide in complex with gamma-mangostin

Summary for 4Y9F

• Entry DOI: 10.2210/pdb4y9f/pdb
• Related: 4PWE 4Y9B 4Y9C 4Y9E 4Y9G
• Descriptor: Transthyretin, 1,3,6,7-tetrahydroxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one, BROMIDE ION, ... (4 entities in total)
• Functional Keywords: transthyretin, inhibitor, natural pruduct, transporter, amyloidosis, transport protein-inhibitor complex, transport protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 36117.26

Authors

Yokoyama, T.,Mizuguchi, M. (deposition date: 2015-02-17, release date: 2015-09-09, Last modification date: 2023-11-08)

Primary citation

Yokoyama, T.,Ueda, M.,Ando, Y.,Mizuguchi, M.
Discovery of gamma-Mangostin as an Amyloidogenesis Inhibitor
Sci Rep, 5:13570-13570, 2015

PubMed Abstract: 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 γ-mangostin (γ-M) is an effective inhibitor against the amyloid fibril formation of V30M amyloidogenic TTR. In-vitro binding assays revealed that γ-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 γ-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 α-mangostin complex, which is a methylated derivative of γ-M. The stronger inhibitory potency of γ-M could be explained by the additional hydrogen bonds with the chloride ion. The present study establishes γ-M as a novel inhibitor of TTR fibrillization.

PubMed: 26310724
DOI: 10.1038/srep13570

Experimental method

X-RAY DIFFRACTION (1.5 Å)