1Y0X

Thyroxine-Thyroid Hormone Receptor Interactions

1Y0X の概要

• エントリーDOI: 10.2210/pdb1y0x/pdb
• 関連するPDBエントリー: 1XZX
• 分子名称: Thyroid hormone receptor beta-1, CACODYLATE ION, 3,5,3',5'-TETRAIODO-L-THYRONINE, ... (4 entities in total)
• 機能のキーワード: hormone/growth factor receptor, hormone-growth factor receptor complex
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P10828
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33312.35

構造登録者

Sandler, B.,Webb, P.,Apriletti, J.W.,Huber, B.R.,Togashi, M.,Cunha Lima, S.T.,Juric, S.,Nilsson, S.,Wagner, R.,Fletterick, R.J.,Baxter, J.D. (登録日: 2004-11-16, 公開日: 2004-12-07, 最終更新日: 2024-04-03)

主引用文献

Sandler, B.,Webb, P.,Apriletti, J.W.,Huber, B.R.,Togashi, M.,Cunha Lima, S.T.,Juric, S.,Nilsson, S.,Wagner, R.,Fletterick, R.J.,Baxter, J.D.
Thyroxine-thyroid hormone receptor interactions.
J.Biol.Chem., 279:55801-55808, 2004

PubMed Abstract: Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha and beta) that bind triiodothyronine (T(3), 3,5,3'-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T(4), 3,5,3',5'-tetraiodo-l-thyronine) with lower affinity. T(4) contains a bulky 5' iodine group absent from T(3). Because T(3) is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5' substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists. We therefore examined how T(4) affects TR activity and conformation. We obtained several lines of evidence (ligand dissociation kinetics, migration on hydrophobic interaction columns, and non-denaturing gels) that TR-T(4) complexes adopt a conformation that differs from TR-T(3) complexes in solution. Nonetheless, T(4) behaves as an agonist in vitro (in effects on coregulator and DNA binding) and in cells, when conversion to T(3) does not contribute to agonist activity. We determined x-ray crystal structures of the TRbeta LBD in complex with T(3) and T(4) at 2.5-A and 3.1-A resolution. Comparison of the structures reveals that TRbeta accommodates T(4) through subtle alterations in the loop connecting helices 11 and 12 and amino acid side chains in the pocket, which, together, enlarge a niche that permits helix 12 to pack over the 5' iodine and complete the coactivator binding surface. While T(3) is the major active TH, our results suggest that T(4) could activate nuclear TRs at appropriate concentrations. The ability of TR to adapt to the 5' extension should be considered in TR ligand design.

PubMed: 15466465
DOI: 10.1074/jbc.M410124200

実験手法

X-RAY DIFFRACTION (3.1 Å)