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Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer.

Iakovleva I, Begum A, Brännström K, Wijsekera A, Nilsson L, Zhang J, Andersson PL, Sauer-Eriksson AE, Olofsson A - PLoS ONE (2016)

Bottom Line: The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body.Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP.Its absorption, metabolism, and potential side-effects are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.

ABSTRACT
Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR's native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed.

No MeSH data available.


Related in: MedlinePlus

(A) The TTR-TBBPA structure shows the orientation of the ligand within the T4 binding sites. (B) Close-up view of the dimer-dimer interface of monomers B and B'. The σA-weighted (m/Fo/−D/Fc/) electron density is contoured at 3 times the root-mean-square value of the map and is shown in orange. To reduce model bias, the TBBPA molecules were excluded from the coordinate file that was subjected to one round of simulated annealing before calculation of the electron density map. The anomalous log-likelihood-gradient (LLG) map shown in dark blue shows the positions of the eight symmetry-related bromine atoms and verifies the modeled orientation of the TBBPA compound in the binding site. HBP1–3 and HBP1'–3' are indicated with numbers.
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pone.0153529.g004: (A) The TTR-TBBPA structure shows the orientation of the ligand within the T4 binding sites. (B) Close-up view of the dimer-dimer interface of monomers B and B'. The σA-weighted (m/Fo/−D/Fc/) electron density is contoured at 3 times the root-mean-square value of the map and is shown in orange. To reduce model bias, the TBBPA molecules were excluded from the coordinate file that was subjected to one round of simulated annealing before calculation of the electron density map. The anomalous log-likelihood-gradient (LLG) map shown in dark blue shows the positions of the eight symmetry-related bromine atoms and verifies the modeled orientation of the TBBPA compound in the binding site. HBP1–3 and HBP1'–3' are indicated with numbers.

Mentions: The T4 molecule contains four iodines. Based on their orientation within the hormone binding site of TTR in the previously solved co-crystal structure, the hormone binding site was divided into an inner and outer cavity comprising three symmetry-related pairs of halogen binding pockets, HBP1 (HBP1'), HBP2 (HBP2'), and HBP3 (HBP3') [29]. The side chains of Met13, Lys15, and Thr106 define the outer pocket HBP1. The middle pocket, HBP2, is composed of the hydrophobic side chains of residues Lys15, Leu17, Ala109, and Leu110, while the main-chain carbonyl groups of Lys15, Ala108, and Ala109 form a hydrophilic surface. The innermost pocket, HBP3, is formed by residues Ala108, Ala109, Leu110, Ser117, Thr118, and Thr119. Like HBP2, HBP3 has a hydrophilic surface consisting of the main-chain carbonyl oxygens and the amino groups of Ala108, Ala109, Leu110, and Thr118 and the polar parts of the Ser117 and Thr119 side chains. In this work, we have co-crystallized human wild-type TTR with TBBPA and solved the structure at a resolution 1.4 Å. Our structure shows that two symmetric TBBPA molecules are buried within the tetramer interface where symmetry-related bromine atoms occupy the three halogen binding pockets, HBP1, HBP2, and HBP3, in the T4 hormone binding site (Fig 4).


Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer.

Iakovleva I, Begum A, Brännström K, Wijsekera A, Nilsson L, Zhang J, Andersson PL, Sauer-Eriksson AE, Olofsson A - PLoS ONE (2016)

(A) The TTR-TBBPA structure shows the orientation of the ligand within the T4 binding sites. (B) Close-up view of the dimer-dimer interface of monomers B and B'. The σA-weighted (m/Fo/−D/Fc/) electron density is contoured at 3 times the root-mean-square value of the map and is shown in orange. To reduce model bias, the TBBPA molecules were excluded from the coordinate file that was subjected to one round of simulated annealing before calculation of the electron density map. The anomalous log-likelihood-gradient (LLG) map shown in dark blue shows the positions of the eight symmetry-related bromine atoms and verifies the modeled orientation of the TBBPA compound in the binding site. HBP1–3 and HBP1'–3' are indicated with numbers.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836675&req=5

pone.0153529.g004: (A) The TTR-TBBPA structure shows the orientation of the ligand within the T4 binding sites. (B) Close-up view of the dimer-dimer interface of monomers B and B'. The σA-weighted (m/Fo/−D/Fc/) electron density is contoured at 3 times the root-mean-square value of the map and is shown in orange. To reduce model bias, the TBBPA molecules were excluded from the coordinate file that was subjected to one round of simulated annealing before calculation of the electron density map. The anomalous log-likelihood-gradient (LLG) map shown in dark blue shows the positions of the eight symmetry-related bromine atoms and verifies the modeled orientation of the TBBPA compound in the binding site. HBP1–3 and HBP1'–3' are indicated with numbers.
Mentions: The T4 molecule contains four iodines. Based on their orientation within the hormone binding site of TTR in the previously solved co-crystal structure, the hormone binding site was divided into an inner and outer cavity comprising three symmetry-related pairs of halogen binding pockets, HBP1 (HBP1'), HBP2 (HBP2'), and HBP3 (HBP3') [29]. The side chains of Met13, Lys15, and Thr106 define the outer pocket HBP1. The middle pocket, HBP2, is composed of the hydrophobic side chains of residues Lys15, Leu17, Ala109, and Leu110, while the main-chain carbonyl groups of Lys15, Ala108, and Ala109 form a hydrophilic surface. The innermost pocket, HBP3, is formed by residues Ala108, Ala109, Leu110, Ser117, Thr118, and Thr119. Like HBP2, HBP3 has a hydrophilic surface consisting of the main-chain carbonyl oxygens and the amino groups of Ala108, Ala109, Leu110, and Thr118 and the polar parts of the Ser117 and Thr119 side chains. In this work, we have co-crystallized human wild-type TTR with TBBPA and solved the structure at a resolution 1.4 Å. Our structure shows that two symmetric TBBPA molecules are buried within the tetramer interface where symmetry-related bromine atoms occupy the three halogen binding pockets, HBP1, HBP2, and HBP3, in the T4 hormone binding site (Fig 4).

Bottom Line: The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body.Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP.Its absorption, metabolism, and potential side-effects are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.

ABSTRACT
Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR's native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed.

No MeSH data available.


Related in: MedlinePlus