Figure 4.

Structure of homotetrameric WT-TTR with a focus on the T₄ binding pocket and pK_a-perturbed Lys15 and 15′ residues. (A) Crystal structure of WT-TTR in complex with T₄ (PDB accession code 2ROX⁵³)(B) Close-up view of one of the two identical T₄ binding sites showing a ribbon depicted tetramer (colored by chain) with a “Connelly” molecular surface applied to residues within 8 Å of T₄ (hydrophobic = grey, polar = purple). The innermost halogen binding pockets (HBPs) 3 and 3′ are composed of the methyl and methylene groups of Ser117/117′, Thr119/119′, and Leu110/110′. HBPs 2 and 2′ are made up by the side chains of Leu110/110′, Ala109/109′, Lys15/15′, and Leu17/17′. The outermost HBPs 1 and 1′ are lined by the methyl and methylene groups of Lys15/15′, Ala108/108′, and Thr106/106′. These figures were generated using the program MOE (2011.10), Chemical Computing Group, Montreal, Canada. (C) Schematic representation of the T₄ binding pocket and the amino acids that are targeted by the substituted (R = CH₃ or Cl) aryl ring A connected by linker X (stilbene or 1,3,4-oxadiazole ring linker) to aryl ring B that contains an electrophile Y (sulfonyl fluoride or fluorophenol thioester) for attack by the pK_a-perturbed nucleophilic ε-amino group of Lys15.