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Transthyretin Binding Mode Dichotomy of Fluorescent trans -Stilbene Ligands.

Afshan BegumJun ZhangDean DerbyshireXiongyu WuPeter KonradssonPer HammarströmEleonore von Castelmur
Published in: ACS chemical neuroscience (2023)
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 trans -stilbene fluorescent ligands, ( E )-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (SB-11) and ( E )-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 trans -stilbene binding modes to the TTR T4 binding site.
Keyphrases
  • dna binding
  • binding protein
  • quantum dots
  • transcription factor
  • living cells
  • molecular dynamics simulations