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Structural evidence for asymmetric ligand binding to transthyretin.

Cianci M, Folli C, Zonta F, Florio P, Berni R, Zanotti G
Acta Crystallogr D Biol Crystallogr 71 1582-92 (2015)
Related entries: 4wns, 4wo0

Cited: 13 times
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Abstract

Human transthyretin (TTR) represents a notable example of an amyloidogenic protein, and several compounds that are able to stabilize its native state have been proposed as effective drugs in the therapy of TTR amyloidosis. The two thyroxine (T4) binding sites present in the TTR tetramer display negative binding cooperativity. Here, structures of TTR in complex with three natural polyphenols (pterostilbene, quercetin and apigenin) have been determined, in which this asymmetry manifests itself as the presence of a main binding site with clear ligand occupancy and related electron density and a second minor site with a much lower ligand occupancy. The results of an analysis of the structural differences between the two binding sites are consistent with such a binding asymmetry. The different ability of TTR ligands to saturate the two T4 binding sites of the tetrameric protein can be ascribed to the different affinity of ligands for the weaker binding site. In comparison, the high-affinity ligand tafamidis, co-crystallized under the same experimental conditions, was able to fully saturate the two T4 binding sites. This asymmetry is characterized by the presence of small but significant differences in the conformation of the cavity of the two binding sites. Molecular-dynamics simulations suggest the presence of even larger differences in solution. Competition binding assays carried out in solution revealed the presence of a preferential binding site in TTR for the polyphenols pterostilbene and quercetin that was different from the preferential binding site for T4. The TTR binding asymmetry could possibly be exploited for the therapy of TTR amyloidosis by using a cocktail of two drugs, each of which exhibits preferential binding for a distinct binding site, thus favouring saturation of the tetrameric protein and consequently its stabilization.

Reviews - 4wnj mentioned but not cited (2)

  1. Natural compounds as inhibitors of transthyretin amyloidosis and neuroprotective agents: analysis of structural data for future drug design. Ciccone L, Tonali N, Nencetti S, Orlandini E. J Enzyme Inhib Med Chem 35 1145-1162 (2020)
  2. Differential Impact of Flavonoids on Redox Modulation, Bioenergetics, and Cell Signaling in Normal and Tumor Cells: A Comprehensive Review. Kerimi A, Williamson G. Antioxid Redox Signal 29 1633-1659 (2018)

Articles - 4wnj mentioned but not cited (1)

  1. Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics. Saldaño TE, Zanotti G, Parisi G, Fernandez-Alberti S. PLoS One 12 e0181019 (2017)


Reviews citing this publication (1)

  1. Impact of oligomerization on the allergenicity of allergens. Hasan-Abad AM, Mohammadi M, Mirzaei H, Mehrabi M, Motedayyen H, Arefnezhad R. Clin Mol Allergy 20 5 (2022)

Articles citing this publication (9)

  1. Transthyretin Binding Heterogeneity and Anti-amyloidogenic Activity of Natural Polyphenols and Their Metabolites. Florio P, Folli C, Cianci M, Del Rio D, Zanotti G, Berni R. J Biol Chem 290 29769-29780 (2015)
  2. Binding of Monovalent and Bivalent Ligands by Transthyretin Causes Different Short- and Long-Distance Conformational Changes. Corazza A, Verona G, Waudby CA, Mangione PP, Bingham R, Uings I, Canetti D, Nocerino P, Taylor GW, Pepys MB, Christodoulou J, Bellotti V. J Med Chem 62 8274-8283 (2019)
  3. A new crystal form of human transthyretin obtained with a curcumin derived ligand. Polsinelli I, Nencetti S, Shepard W, Ciccone L, Orlandini E, Stura EA. J Struct Biol 194 8-17 (2016)
  4. Synthesis and structural analysis of halogen substituted fibril formation inhibitors of Human Transthyretin (TTR). Ciccone L, Nencetti S, Rossello A, Stura EA, Orlandini E. J Enzyme Inhib Med Chem 31 40-51 (2016)
  5. Computational study of pH-dependent oligomerization and ligand binding in Alt a 1, a highly allergenic protein with a unique fold. Garrido-Arandia M, Garrido-Arandia M, Bretones J, Gómez-Casado C, Cubells N, Díaz-Perales A, Pacios LF. J Comput Aided Mol Des 30 365-379 (2016)
  6. Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer. Zanotti G, Vallese F, Ferrari A, Menozzi I, Saldaño TE, Berto P, Fernandez-Alberti S, Berni R. PLoS One 12 e0187716 (2017)
  7. Asymmetric ligand binding in homodimeric Enterobacter cloacae nitroreductase yields the Michaelis complex for nitroaromatic substrates. Christofferson AJ. J Mol Model 26 28 (2020)
  8. Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations. Dongmo Foumthuim CJ, Corazza A, Berni R, Esposito G, Fogolari F. Biomed Res Int 2018 7480749 (2018)
  9. Structure and Molecular Dynamics Simulations of Protein Tyrosine Phosphatase Non-Receptor 12 Provide Insights into the Catalytic Mechanism of the Enzyme. Dong H, Zonta F, Wang S, Song K, He X, He M, Nie Y, Li S. Int J Mol Sci 19 (2017)


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