Phelan Caroline A, Weaver Joseph M, Steger David J, Joshi Shree, Maslany Jeffrey T, Collins Jon L, Zuercher William J, Willson Timothy M, Walker Max, Jaye Michael, Lazar Mitchell A
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Mol Endocrinol. 2008 Oct;22(10):2241-9. doi: 10.1210/me.2008-0041. Epub 2008 Jul 31.
Classically, activated transcription by nuclear receptors (NRs) is due to a ligand-induced switch from corepressor- to coactivator-bound states. However, coactivators and corepressors recognize overlapping surfaces of liganded and unliganded NRs, respectively. Here we show that, at sufficiently high concentration, the NR corepressor (NCoR) influences the activity of the liver X receptor (LXR) even in the presence of a potent full agonist that destabilizes NCoR binding. Partial agonist ligands that less effectively dissociate NCoR from LXR are even more sensitive to NCoR levels, in a target gene-selective manner. Thus, differential recruitment of NCoR is a major determinant of partial agonism and selective LXR modulation of target genes.
传统上，核受体（NRs）激活转录是由于配体诱导从共抑制因子结合状态转变为共激活因子结合状态。然而，共激活因子和共抑制因子分别识别结合配体和未结合配体的NRs的重叠表面。我们在此表明，在足够高的浓度下，即使存在使NCoR结合不稳定的强效完全激动剂，NR共抑制因子（NCoR）仍会影响肝脏X受体（LXR）的活性。以靶基因选择性的方式，从LXR上解离NCoR效率较低的部分激动剂配体对NCoR水平更为敏感。因此，NCoR的差异募集是部分激动作用和LXR对靶基因选择性调节的主要决定因素。
