5JIM

Crystal Structure of Human Transthyretin in Complex with Perfluoroktansulfonsyra (PFOS)

5JIM の概要

• エントリーDOI: 10.2210/pdb5jim/pdb
• 関連するPDBエントリー: 5HJG 5JID
• 分子名称: Transthyretin, heptadecafluoro-1-octanesulfonic acid, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: transport protein, thyroxine binding, perfluoroktansulfonsyra (pfos)complex
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted: P02766
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28577.97

構造登録者

Begum, A.,Zhang, J.,Olofsson, A.,Andersson, P.,Sauer-Eriksson, A.E. (登録日: 2016-04-22, 公開日: 2016-10-05, 最終更新日: 2024-01-10)

主引用文献

Zhang, J.,Begum, A.,Brannstrom, K.,Grundstrom, C.,Iakovleva, I.,Olofsson, A.,Sauer-Eriksson, A.E.,Andersson, P.L.
Structure-Based Virtual Screening Protocol for in Silico Identification of Potential Thyroid Disrupting Chemicals Targeting Transthyretin.
Environ. Sci. Technol., 50:11984-11993, 2016

PubMed Abstract: Thyroid disruption by xenobiotics is associated with a broad spectrum of severe adverse outcomes. One possible molecular target of thyroid hormone disrupting chemicals (THDCs) is transthyretin (TTR), a thyroid hormone transporter in vertebrates. To better understand the interactions between TTR and THDCs, we determined the crystallographic structures of human TTR in complex with perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2,2',4,4'-tetrahydroxybenzophenone (BP2). The molecular interactions between the ligands and TTR were further characterized using molecular dynamics simulations. A structure-based virtual screening (VS) protocol was developed with the intention of providing an efficient tool for the discovery of novel TTR-binders from the Tox21 inventory. Among the 192 predicted binders, 12 representatives were selected, and their TTR binding affinities were studied with isothermal titration calorimetry, of which seven compounds had binding affinities between 0.26 and 100 μM. To elucidate structural details in their binding to TTR, crystal structures were determined of TTR in complex with four of the identified compounds including 2,6-dinitro-p-cresol, bisphenol S, clonixin, and triclopyr. The compounds were found to bind in the TTR hormone binding sites as predicted. Our results show that the developed VS protocol is able to successfully identify potential THDCs, and we suggest that it can be used to propose THDCs for future toxicological evaluations.

PubMed: 27668830
DOI: 10.1021/acs.est.6b02771

実験手法

X-RAY DIFFRACTION (1.26 Å)