Effect of heterodimer partner RXRα on PPARγ activation function-2 helix in solution
Effect of heterodimer partner RXRα on PPARγ activation function-2 helix in solution
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DOI：
10.1016/j.bbrc.2007.10.143
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发表时间：
2008-01-04
影响因子：
3.1
通讯作者：
Li, Ellen
中科院分区：
文献类型：
--
作者：
Lu, Jianyun;Chen, Minghe;Li, Ellen
维甲酸X受体（RXR）与其异源二聚体之间的变构通讯的结构机制仍存在争议。作为解决这个问题的第一步，我们报告了一个核磁共振（NMR）研究GW 1929结合过氧化物酶体增殖物激活受体γ（PPAR γ）配体结合域（LBD）与9-顺式维甲酸（9 cRA）结合RXR α LBD和不。已为PPAR γ LBD单体中超过95%的275个残基建立了序列特异性C-13（α）、C-13（β）和（CO）-C-13共振归属。由RXR α LBD结合诱导的（HN）-H-1、N-15和（CO）-C-13化学位移扰动不仅位于异二聚体界面，该界面包括C-末端残基Y 477，还包括激活功能-2（AF-2）螺旋中的残基Y 473和K474。这一结果表明，9 cRA结合的RXR α可以影响溶液中的PPAR γ AF-2螺旋，并表明NMR是研究RXR异二聚体中变构配体活化机制的有力新工具。由爱思唯尔公司出版
The structural mechanism of allosteric communication between retinoid X receptor (RXR) and its heterodimer partners remains controversial. As a first step towards addressing this question, we report a nuclear magnetic resonance (NMR) study on the GW1929-bound peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand-binding domain (LBD) with and without the 9-cis-retinoic acid (9cRA)-bound RXR alpha LBD. Sequence-specific C-13(alpha), C-13(beta), and (CO)-C-13 resonance assignments have been established for over 95% of the 275 residues in the PPAR gamma LBD monomer. The (HN)-H-1, N-15, and (CO)-C-13 chemical shift perturbations induced by the RXR alpha LBD binding are located at not only the heterodimer interface that includes the C-terminal residue Y477 but also residues Y473 and K474 in the activation function-2 (AF-2) helix. This result suggests that 9cRA-bound RXR alpha can affect the PPAR gamma AF-2 helix in solution and demonstrates that NMR is a powerful new tool for studying the mechanism of allosteric ligand activation in RXR heterodimers. Published by Elsevier Inc.