Structure of a Thyroid Hormone Receptor DNA-Binding Domain Homodimer Bound to an Inverted Palindrome DNA Response Element
Structure of a Thyroid Hormone Receptor DNA-Binding Domain Homodimer Bound to an Inverted Palindrome DNA Response Element
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DOI：
10.1210/me.2010-0129
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发表时间：
2010-08-01
影响因子：
--
通讯作者：
Young, Matthew A.
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文献类型：
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作者：
Chen, Yi;Young, Matthew A.
甲状腺激素受体 (TR) 作为核激素受体家族的一员，可以识别并结合不同类别的 DNA 反应元件靶标，无论是单体、同源寡聚体还是异源寡聚体。我们在此报告了同型二聚体 TR DNA 结合域 (DBD) 与甲状腺反应元件 (TRE) 反向重复序列复合物的第一个晶体结构。该结构显示了在 F2 TRE 上组装的 TR DBD 的近对称结构，其中同二聚体 DNA 复合物中的碱基识别接触相对于先前公布的 TR-9-顺式-视黄酸受体异二聚体 DNA 复合物的结构是保守的。新结构还表明，DBD 的 T 盒区域可以充当结构铰链，使连接 DBD 和配体结合域的 C 端延伸螺旋的位置具有很大程度的灵活性。尽管分离的 TR DBD 在溶液中以单体形式存在，但我们测量了两个 TR DBD 亚基与反向重复 DNA 序列的高度协同结合。这表明 DBD 的元件可以影响靶基因上的特定 TR 寡聚化，并且不仅仅是配体结合结构域之间的相互作用负责靶基因上的 TR 寡聚化。突变分析表明，DBD C 末端的亚基间接触部分（但不是全部）解释了协同同源二聚体 TR 与反向重复序列 TRE 的结合。 （分子内分泌学24：1650-1664，2010）
Thyroid hormone receptor (TR), as a member of the nuclear hormone receptor family, can recognize and bind different classes of DNA response element targets as either a monomer, a homooligomer, or a heterooligomer. We report here the first crystal structure of a homodimer TR DNA-binding domain (DBD) in complex with an inverted repeat class of thyroid response element (TRE). The structure shows a nearly symmetric structure of the TR DBD assembled on the F2 TRE where the base recognition contacts in the homodimer DNA complex are conserved relative to the previously published structure of a TR-9-cis-retinoic acid receptor heterodimer DNA complex. The new structure also reveals that the T-box region of the DBD can function as a structural hinge that enables a large degree of flexibility in the position of the C-terminal extension helix that connects the DBD to the ligand-binding domain. Although the isolated TR DBDs exist as monomers in solution, we have measured highly cooperative binding of the two TR DBD subunits onto the inverted repeat DNA sequence. This suggests that elements of the DBD can influence the specific TR oligomerization at target genes, and it is not just interactions between the ligand-binding domains that are responsible for TR oligomerization at target genes. Mutational analysis shows that intersubunit contacts at the DBD C terminus account for some, but not all, of the cooperative homodimer TR binding to the inverted repeat class TRE. (Molecular Endocrinology 24: 1650-1664, 2010)