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首页> 外文期刊>Biochemistry >Structure, Energetics, and Dynamics of Binding Coactivator Peptide to the Human Retinoid X Receptor alpha Ligand Binding Domain Complex with 9-cis-Retinoic Acid
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Structure, Energetics, and Dynamics of Binding Coactivator Peptide to the Human Retinoid X Receptor alpha Ligand Binding Domain Complex with 9-cis-Retinoic Acid

机译：结构，能量学和动力学与9-顺式视黄酸人类类视黄醇X受体α配体结合域复合物的结合激活因子​​肽的动力学。

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摘要

Retinoid X receptors (RXRs) are ligand-dependent nuclear receptors, which are activated by the potent agonist 9-cis-retinoic acid (9cRA). 9cRA binds to the ligand binding domain (LBD) of RXRs and recruits coactivator proteins for gene transcription. Using isothermal titration calorimetry, the binding of a 13-mer coactivator peptide, GRIP-1, to the hRXR alpha-LBD homodimer complex containing 9cRA (hRXR alpha-LBD:9cRA:GRIP-1) is reported between 20 and 37 degrees C. Delta G is temperature independent (-8.5 kcal/mol), and GRIP-1 binding is driven by Delta H (-9.2 kcal/mol) at 25 degrees C. Delta C-p is large and negative (-401 cal mol(-1) K-1). The crystal structure of hRXR alpha-LBD:9cRA:GRIP-1 is reported at 2.05 angstrom. When the structures of hRXR alpha-LBD:9cRA:GRIP-1 and hRXR alpha-LBD:9cRA (1FBY) homodimers are compared, E453 and E456 on helix 12 bury and form ionic interactions with GRIP-1. R302 on helix 4 realigns to form new salt bridges to both E453 and E456. F277 (helix 3), F437 (helix 11), and F450 (helix 12) move toward the hydrophobic interior. The changes in the near-UV spectrum at 260 nm of the hRXR alpha-LBD:9cRA:GRIP-1 support this structural change. Helix 11 tilts toward helix 12 by approximate to 1 angstrom, modifying the ring conformation of 9cRA. Hydrogen-deuterium exchange mass spectroscopy indicates GRIP-1 binding to hRXR alpha-LBD:9cRA significantly decreases the exchange rates for peptides containing helices 3 (F277), 4 (R302), 11 (F437), and 12 (E453, E456). The structural changes and loss of dynamics of the GRIP-1-bound structure are used to interpret the energetics of coactivator peptide binding to the agonist-bound hRXR alpha-LBD.
机译：类视黄醇X受体（RXRs）是依赖配体的核受体，其被强效激动剂9-顺-视黄酸（9cRA）激活。 9cRA与RXR的配体结合域（LBD）结合，并募集辅助激活蛋白进行基因转录。使用等温滴定量热法，据报道在20至37摄氏度之间，一个13-mer共激活肽GRIP-1与包含9cRA（hRXR alpha-LBD：9cRA：GRIP-1）的hRXR alpha-LBD同型二聚体复合物的结合。 ΔG与温度无关（-8.5 kcal / mol），并且GRIP-1结合由25°C下的Delta H（-9.2 kcal / mol）驱动.Delta Cp大而为负（-401 cal mol（-1） K-1）。据报道，hRXRα-LBD：9cRA：GRIP-1的晶体结构为2.05埃。比较hRXR alpha-LBD：9cRA：GRIP-1和hRXR alpha-LBD：9cRA（1FBY）同型二聚体的结构时，螺旋12上的E453和E456掩埋并与GRIP-1形成离子相互作用。螺旋4上的R302重新排列以形成通往E453和E456的新盐桥。 F277（螺旋3），F437（螺旋11）和F450（螺旋12）向疏水内部移动。 hRXR alpha-LBD：9cRA：GRIP-1在260 nm处的近紫外光谱变化支持这种结构变化。螺旋11向螺旋12倾斜大约1埃，从而修饰了9cRA的环构象。氢-氘交换质谱表明GRIP-1与hRXR alpha-LBD：9cRA的结合显着降低了含有螺旋3（F277），4（R302），11（F437）和12（E453，E456）的肽的交换速率。 GRIP-1结合结构的结构变化和动力学损失被用来解释与激动剂结合的hRXRα-LBD结合的共激活肽的能量。

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