4N87

Crystal structure of V30M mutant human transthyretin complexed with glabridin

Summary for 4N87

• Entry DOI: 10.2210/pdb4n87/pdb
• Related: 4N85 4N86
• Descriptor: Transthyretin, 4-[(3R)-8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl]benzene-1,3-diol (3 entities in total)
• Functional Keywords: transporter, thyroxine binding, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 35333.90

Authors

Yokoyama, T.,Kosaka, Y.,Mizuguchi, M. (deposition date: 2013-10-17, release date: 2014-02-19, Last modification date: 2024-03-20)

Primary citation

Yokoyama, T.,Kosaka, Y.,Mizuguchi, M.
Crystal structures of human transthyretin complexed with glabridin
J.Med.Chem., 57:1090-1096, 2014

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.

PubMed: 24422526
DOI: 10.1021/jm401832j

Experimental method

X-RAY DIFFRACTION (1.794 Å)