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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

Molecular interaction between TBBPA and TTR at the B—B' hormone-binding site.Carbon atoms from the B monomer and TBBPA are colored in blue, and carbon atoms from the B' monomer are colored in yellow. Lys15 and Leu17 have two rotamer conformations (conf1 and conf2), of which only the ones interacting with the bound TBBPA ligand are shown. The Nz atom of the B'-Lys15 side chain forms a hydrogen bond with a water molecule and the O5 atom of the TBBPA ligand, whereas the Nz atom of B-Lys15 adopts a different orientation to allow for a hydrophobic interaction with the TBBPA benzene ring. The side chain of Ser117 has three rotamer conformations of which one (occupancy 25%) makes a hydrogen bond to the same residue in the A monomer. The HBP1–3 and HBP1'–3' binding sites are indicated with black numbers, and bromine atoms are colored in purple.
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pone.0153529.g005: Molecular interaction between TBBPA and TTR at the B—B' hormone-binding site.Carbon atoms from the B monomer and TBBPA are colored in blue, and carbon atoms from the B' monomer are colored in yellow. Lys15 and Leu17 have two rotamer conformations (conf1 and conf2), of which only the ones interacting with the bound TBBPA ligand are shown. The Nz atom of the B'-Lys15 side chain forms a hydrogen bond with a water molecule and the O5 atom of the TBBPA ligand, whereas the Nz atom of B-Lys15 adopts a different orientation to allow for a hydrophobic interaction with the TBBPA benzene ring. The side chain of Ser117 has three rotamer conformations of which one (occupancy 25%) makes a hydrogen bond to the same residue in the A monomer. The HBP1–3 and HBP1'–3' binding sites are indicated with black numbers, and bromine atoms are colored in purple.

Mentions: The bend of the TBBPA molecule at the central gem-dimethyl group is accommodated in the T4 binding site by a ligand-induced rotamer conformational change of the Leu17 side chain (Fig 5). Furthermore, the position of the hydroxyl group on the outer side of the cavity (HBP3 and HBP3') is stabilized by a hydrogen bond to Lys15 that also occupies two rotamer conformations in the structure (Fig 5).


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)

Molecular interaction between TBBPA and TTR at the B—B' hormone-binding site.Carbon atoms from the B monomer and TBBPA are colored in blue, and carbon atoms from the B' monomer are colored in yellow. Lys15 and Leu17 have two rotamer conformations (conf1 and conf2), of which only the ones interacting with the bound TBBPA ligand are shown. The Nz atom of the B'-Lys15 side chain forms a hydrogen bond with a water molecule and the O5 atom of the TBBPA ligand, whereas the Nz atom of B-Lys15 adopts a different orientation to allow for a hydrophobic interaction with the TBBPA benzene ring. The side chain of Ser117 has three rotamer conformations of which one (occupancy 25%) makes a hydrogen bond to the same residue in the A monomer. The HBP1–3 and HBP1'–3' binding sites are indicated with black numbers, and bromine atoms are colored in purple.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0153529.g005: Molecular interaction between TBBPA and TTR at the B—B' hormone-binding site.Carbon atoms from the B monomer and TBBPA are colored in blue, and carbon atoms from the B' monomer are colored in yellow. Lys15 and Leu17 have two rotamer conformations (conf1 and conf2), of which only the ones interacting with the bound TBBPA ligand are shown. The Nz atom of the B'-Lys15 side chain forms a hydrogen bond with a water molecule and the O5 atom of the TBBPA ligand, whereas the Nz atom of B-Lys15 adopts a different orientation to allow for a hydrophobic interaction with the TBBPA benzene ring. The side chain of Ser117 has three rotamer conformations of which one (occupancy 25%) makes a hydrogen bond to the same residue in the A monomer. The HBP1–3 and HBP1'–3' binding sites are indicated with black numbers, and bromine atoms are colored in purple.
Mentions: The bend of the TBBPA molecule at the central gem-dimethyl group is accommodated in the T4 binding site by a ligand-induced rotamer conformational change of the Leu17 side chain (Fig 5). Furthermore, the position of the hydroxyl group on the outer side of the cavity (HBP3 and HBP3') is stabilized by a hydrogen bond to Lys15 that also occupies two rotamer conformations in the structure (Fig 5).

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