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4LNW

Crystal structure of TR-alpha bound to T3 in a second site

4LNW の概要
エントリーDOI10.2210/pdb4lnw/pdb
関連するPDBエントリー3ILZ 3JZB 4LNX
分子名称Thyroid hormone receptor alpha, 3,5,3'TRIIODOTHYRONINE (3 entities in total)
機能のキーワードmainly alpha orthogonal bundle, transcription factor, transcription
由来する生物種Homo sapiens (human)
細胞内の位置Nucleus: P10827
タンパク質・核酸の鎖数1
化学式量合計32079.89
構造登録者
Puhl, A.C.,Aparicio, R.,Polikarpov, I. (登録日: 2013-07-12, 公開日: 2014-03-19, 最終更新日: 2023-11-15)
主引用文献Souza, P.C.,Puhl, A.C.,Martinez, L.,Aparicio, R.,Nascimento, A.S.,Figueira, A.C.,Nguyen, P.,Webb, P.,Skaf, M.S.,Polikarpov, I.
Identification of a new hormone-binding site on the surface of thyroid hormone receptor.
Mol.Endocrinol., 28:534-545, 2014
Cited by
PubMed Abstract: Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many nuclear receptor ligand-binding domains (LBDs) reveal that the ligand binds within the hydrophobic core of the ligand-binding pocket, a few studies suggest the possibility of ligands binding to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T3 and T4 located between H9, H10, and H11 of the TRα LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics simulations to investigate ligand mobility and ligand-protein interaction for T3 and T4 bound to this new TR surface-binding site. Extensive molecular dynamics simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions.
PubMed: 24552590
DOI: 10.1210/me.2013-1359
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.9 Å)
構造検証レポート
Validation report summary of 4lnw
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-04-02に公開中

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