Westin S, Kurokawa R, Nolte R T, Wisely G B, McInerney E M, Rose D W, Milburn M V, Rosenfeld M G, Glass C K
Division of Cellular and Molecular Medicine, University of California, San Diego, La Jolla 92093-0651, USA.
Nature. 1998 Sep 10;395(6698):199-202. doi: 10.1038/26040.
Retinoic-acid receptor-alpha (RAR-alpha) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are members of the nuclear-receptor superfamily that bind to DNA as heterodimers with retinoid-X receptors (RXRs). PPAR-RXR heterodimers can be activated by PPAR or RXR ligands, whereas RAR-RXR heterodimers are selectively activated by RAR ligands only, because of allosteric inhibition of the binding of ligands to RXR by RAR. However, RXR ligands can potentiate the transcriptional effects of RAR ligands in cells. Transcriptional activation by nuclear receptors requires a carboxy-terminal helical region, termed activation function-2 (AF-2), that forms part of the ligand-binding pocket and undergoes a conformational change required for the recruitment of co-activator proteins, including NCoA-1/SRC-1. Here we show that allosteric inhibition of RXR results from a rotation of the RXR AF-2 helix that places it in contact with the RAR coactivator-binding site. Recruitment of an LXXLL motif of SRC-1 to RAR in response to ligand displaces the RXR AF-2 domain, allowing RXR ligands to bind and promote the binding of a second LXXLL motif from the same SRC-1 molecule. These results may partly explain the different responses of nuclear-receptor heterodimers to RXR-specific ligands.
维甲酸受体α（RAR-α）和过氧化物酶体增殖物激活受体γ（PPAR-γ）是核受体超家族的成员，它们作为与视黄酸X受体（RXR）的异二聚体与DNA结合。PPAR-RXR异二聚体可被PPAR或RXR配体激活，而RAR-RXR异二聚体仅被RAR配体选择性激活，因为RAR对配体与RXR结合具有变构抑制作用。然而，RXR配体可增强细胞中RAR配体的转录效应。核受体的转录激活需要一个羧基末端螺旋区域，称为激活功能-2（AF-2），它构成配体结合口袋的一部分，并经历招募包括NCoA-1/SRC-1在内的共激活蛋白所需的构象变化。我们在此表明，RXR的变构抑制源于RXR AF-2螺旋的旋转，使其与RAR共激活剂结合位点接触。响应配体时，SRC-1的LXXLL基序被招募到RAR会取代RXR AF-2结构域，从而使RXR配体能够结合并促进来自同一SRC-1分子的第二个LXXLL基序的结合。这些结果可能部分解释了核受体异二聚体对RXR特异性配体的不同反应。
