3cfn › Citations

Identification of a novel ligand binding motif in the transthyretin channel.

Lima LM, Silva Vde A, Palmieri Lde C, Oliveira MC, Foguel D, Polikarpov I
Bioorg Med Chem 18 100-10 (2010)
Related entries: 3cfm, 3cfq, 3cft

Cited: 14 times
EuropePMC logo PMID: 19954984

Abstract

The design of therapeutic compounds targeting transthyretin (TTR) is challenging due to the low specificity of interaction in the hormone binding site. Such feature is highlighted by the interactions of TTR with diclofenac, a compound with high affinity for TTR, in two dissimilar modes, as evidenced by crystal structure of the complex. We report here structural analysis of the interactions of TTR with two small molecules, 1-amino-5-naphthalene sulfonate (1,5-AmNS) and 1-anilino-8-naphthalene sulfonate (1,8-ANS). Crystal structure of TTR:1,8-ANS complex reveals a peculiar interaction, through the stacking of the naphthalene ring between the side-chain of Lys15 and Leu17. The sulfonate moiety provides additional interaction with Lys15' and a water-mediated hydrogen bond with Thr119'. The uniqueness of this mode of ligand recognition is corroborated by the crystal structure of TTR in complex with the weak analogue 1,5-AmNS, the binding of which is driven mainly by hydrophobic partition and one electrostatic interaction between the sulfonate group and the Lys15. The ligand binding motif unraveled by 1,8-ANS may open new possibilities to treat TTR amyloid diseases by the elucidation of novel candidates for a more specific pharmacophoric pattern.

Articles - 3cfn mentioned but not cited (1)

  1. Ligand binding remodels protein side-chain conformational heterogeneity. Wankowicz SA, de Oliveira SH, Hogan DW, van den Bedem H, Fraser JS. Elife 11 e74114 (2022)


Reviews citing this publication (1)

  1. Boron in drug discovery: carboranes as unique pharmacophores in biologically active compounds. Issa F, Kassiou M, Rendina LM. Chem Rev 111 5701-5722 (2011)

Articles citing this publication (12)

  1. Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate. Grimster NP, Connelly S, Baranczak A, Dong J, Krasnova LB, Sharpless KB, Powers ET, Wilson IA, Kelly JW. J Am Chem Soc 135 5656-5668 (2013)
  2. Identification of beta-amyloid-binding sites on transthyretin. Du J, Cho PY, Yang DT, Murphy RM. Protein Eng Des Sel 25 337-345 (2012)
  3. A fluorogenic aryl fluorosulfate for intraorganellar transthyretin imaging in living cells and in Caenorhabditis elegans. Baranczak A, Liu Y, Connelly S, Du WG, Greiner ER, Genereux JC, Wiseman RL, Eisele YS, Bradbury NC, Dong J, Noodleman L, Sharpless KB, Wilson IA, Encalada SE, Kelly JW. J Am Chem Soc 137 7404-7414 (2015)
  4. Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis. Miller M, Pal A, Albusairi W, Joo H, Pappas B, Haque Tuhin MT, Liang D, Jampala R, Liu F, Khan J, Faaij M, Park M, Chan W, Graef I, Zamboni R, Kumar N, Fox J, Sinha U, Alhamadsheh M. J Med Chem 61 7862-7876 (2018)
  5. Inhibition of human transthyretin aggregation by non-steroidal anti-inflammatory compounds: a structural and thermodynamic analysis. Sant'anna RO, Braga CA, Polikarpov I, Ventura S, Lima LM, Foguel D. Int J Mol Sci 14 5284-5311 (2013)
  6. Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors. Zanotti G, Cendron L, Folli C, Florio P, Imbimbo BP, Berni R. FEBS Lett 587 2325-2331 (2013)
  7. The putative role of some conserved water molecules in the structure and function of human transthyretin. Banerjee A, Dasgupta S, Mukhopadhyay BP, Sekar K. Acta Crystallogr D Biol Crystallogr 71 2248-2266 (2015)
  8. 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)
  9. Conserved water mediated H-bonding dynamics of Ser117 and Thr119 residues in human transthyretin-thyroxin complexation: inhibitor modeling study through docking and molecular dynamics simulation. Banerjee A, Bairagya HR, Mukhopadhyay BP, Nandi TK, Mishra DK. J Mol Graph Model 44 70-80 (2013)
  10. Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations. Cao H, Sun Y, Wang L, Zhao C, Fu J, Zhang A. Mol Biosyst 13 736-749 (2017)
  11. X-ray crystal structure and activity of fluorenyl-based compounds as transthyretin fibrillogenesis inhibitors. Ciccone L, Nencetti S, Rossello A, Tepshi L, Stura EA, Orlandini E. J Enzyme Inhib Med Chem 31 824-833 (2016)
  12. An insight to the conserved water mediated dynamics of catalytic His88 and its recognition to thyroxin and RBP binding residues in human transthyretin. Banerjee A, Mukhopadhyay BP. J Biomol Struct Dyn 33 1973-1988 (2015)


Quick links