2XN5

Crystal structure of thyroxine-binding globulin complexed with Furosemide

2XN5 の概要

• エントリーDOI: 10.2210/pdb2xn5/pdb
• 関連するPDBエントリー: 2CEO 2RIV 2RIW 2XN3 2XN6 2XN7
• 分子名称: THYROXINE-BINDING GLOBULIN, 5-(AMINOSULFONYL)-4-CHLORO-2-[(2-FURYLMETHYL)AMINO]BENZOIC ACID, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: transport, cleaved protein
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Secreted: P05543 P05543
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43912.02

構造登録者

Qi, X.,Yan, Y.,Wei, Z.,Zhou, A. (登録日: 2010-07-30, 公開日: 2011-02-16, 最終更新日: 2023-12-20)

主引用文献

Qi, X.,Loiseau, F.,Chan, W.L.,Yan, Y.,Wei, Z.,Milroy, L.G.,Myers, R.M.,Ley, S.V.,Read, R.J.,Carrell, R.W.,Zhou, A.
Allosteric Modulation of Hormone Release from Thyroxine and Corticosteroid Binding-Globulins.
J.Biol.Chem., 286:16163-, 2011

PubMed Abstract: The release of hormones from thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG) is regulated by movement of the reactive center loop in and out of the β-sheet A of the molecule. To investigate how these changes are transmitted to the hormone-binding site, we developed a sensitive assay using a synthesized thyroxine fluorophore and solved the crystal structures of reactive loop cleaved TBG together with its complexes with thyroxine, the thyroxine fluorophores, furosemide, and mefenamic acid. Cleavage of the reactive loop results in its complete insertion into the β-sheet A and a substantial but incomplete decrease in binding affinity in both TBG and CBG. We show here that the direct interaction between residue Thr(342) of the reactive loop and Tyr(241) of the hormone binding site contributes to thyroxine binding and release following reactive loop insertion. However, a much larger effect occurs allosterically due to stretching of the connecting loop to the top of the D helix (hD), as confirmed in TBG with shortening of the loop by three residues, making it insensitive to the S-to-R transition. The transmission of the changes in the hD loop to the binding pocket is seen to involve coherent movements in the s2/3B loop linked to the hD loop by Lys(243), which is, in turn, linked to the s4/5B loop, flanking the thyroxine-binding site, by Arg(378). Overall, the coordinated movements of the reactive loop, hD, and the hormone binding site allow the allosteric regulation of hormone release, as with the modulation demonstrated here in response to changes in temperature.

PubMed: 21325280
DOI: 10.1074/JBC.M110.171082

実験手法

X-RAY DIFFRACTION (1.7 Å)