8AWI

Crystal structure of Human Transthyretin at 1.15 Angstrom resolution

Summary for 8AWI

• Entry DOI: 10.2210/pdb8awi/pdb
• Descriptor: Transthyretin, SODIUM ION (3 entities in total)
• Functional Keywords: transthyretin, hormone-binding protein, thyroxine, transport, fluorescence, amyloid, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 26227.36

Authors

Derbyshire, D.J.,Hammarstrom, P.,von Castelmur, E.,Begum, A. (deposition date: 2022-08-29, release date: 2023-03-01, Last modification date: 2024-05-01)

Primary citation

Begum, A.,Zhang, J.,Derbyshire, D.,Wu, X.,Konradsson, P.,Hammarstrom, P.,von Castelmur, E.
Transthyretin Binding Mode Dichotomy of Fluorescent trans -Stilbene Ligands.
Acs Chem Neurosci, 14:820-828, 2023

PubMed Abstract: The orientations of ligands bound to the transthyretin (TTR) thyroxine (T4) binding site are difficult to predict. Conflicting binding modes of resveratrol have been reported. We previously reported two resveratrol based -stilbene fluorescent ligands, ()-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (SB-11) and ()-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (SB-14), that bind native and misfolded protofibrillar TTR. The binding orientations of these two analogous ligands to native tetrameric TTR were predicted to be opposite. Herein we report the crystal structures of these TTR:ligand complexes. Opposite binding modes were verified but were different than predicted. The reverse binding mode (SB-14) placing the naphthalene moiety toward the opening of the binding pocket renders the fluorescent ligand pH sensitive due to changes in Lys15 amine protonation. Conversely, the forward binding mode (SB-11) placing the naphthalene inward mediates a stabilizing conformational change, allowing intersubunit H-bonding between Ser117 of different monomers across the dimer interface. Our structures of TTR complexes answer important questions in ligand design and interpretation of -stilbene binding modes to the TTR T4 binding site.

PubMed: 36780206
DOI: 10.1021/acschemneuro.2c00700

Experimental method

X-RAY DIFFRACTION (1.15 Å)