7QC5

Crystal structure of human wild type transthyretin in complex with (3,4-dihydroxy-5-nitrophenyl)-(3-fluoro-5-hydroxyphenyl)methanone compound

7QC5 の概要

• エントリーDOI: 10.2210/pdb7qc5/pdb
• 分子名称: Transthyretin, (3-fluoranyl-5-oxidanyl-phenyl)-[3-nitro-4,5-bis(oxidanyl)phenyl]methanone (3 entities in total)
• 機能のキーワード: thyroxine (t4) binding site, stabilization compound, amyloid fibrils., transport protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28141.13

構造登録者

Varejao, N.,Pinheiro, F.,Pallares, I.,Ventura, S.,Reverter, D. (登録日: 2021-11-22, 公開日: 2022-11-30, 最終更新日: 2024-01-31)

主引用文献

Pinheiro, F.,Pallares, I.,Peccati, F.,Sanchez-Morales, A.,Varejao, N.,Bezerra, F.,Ortega-Alarcon, D.,Gonzalez, D.,Osorio, M.,Navarro, S.,Velazquez-Campoy, A.,Almeida, M.R.,Reverter, D.,Busque, F.,Alibes, R.,Sodupe, M.,Ventura, S.
Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation.
J.Med.Chem., 65:14673-14691, 2022

PubMed Abstract: Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, displays one of the highest affinities for TTR described so far. The TTR/ crystal structure confirmed the formation of unprecedented protein-ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like , hold the potential to become highly potent drugs to treat ATTR.

PubMed: 36306808
DOI: 10.1021/acs.jmedchem.2c01195

実験手法

X-RAY DIFFRACTION (1.2 Å)