Novel interactions of the mineralocorticoid receptor
Novel interactions of the mineralocorticoid receptor
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DOI：
10.1016/j.mce.2015.01.027
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发表时间：
2015-06-15
影响因子：
4.1
通讯作者：
Fuller, Peter J.
中科院分区：
文献类型：
--
作者：
Fuller, Peter J.
盐皮质激素受体(MR)与其他类固醇受体的不同之处在于，它对两种生理配体--醛固酮和皮质醇产生反应。在上皮组织中，醛固酮的选择性由11β-羟基类固醇脱氢酶II型决定。在其他组织中，皮质醇是主要的配体；在某些组织中，皮质醇可能起到拮抗剂的作用。为了更好地靶向MR，需要了解组织和配体特异性MR激活的结构决定因素。我们的重点是配体结合结构域(LBD)与配体、N-末端结构域和可能的共调控分子的相互作用。分子模拟已经在MR和其他类固醇受体的LBD中确定了一个区域，该区域关键地定义了醛固酮和皮质醇的配体特异性，但不是配体结合口袋的一部分。在MR中观察到的N末端与LBD之间的相互作用是醛固酮依赖的，但出人意料地被皮质醇拮抗。这种相互作用的结构基础已经被定义。我们已经确定了在醛固酮或皮质醇存在的情况下相互作用的蛋白质，但不是两者都有。这些已被证实为全长HMR的共激活子。这种相互作用的结构基础已经被确定为MR的配体识别共激活剂Tesmin。成功地鉴定MR的拮抗和配体特异性相互作用的结构基础可能为开发具有组织特异性的新型MR配体提供基础。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
The mineralocorticoid receptor (MR) differs from the other steroid receptors in that it responds to two physiological ligands, aldosterone and cortisol. In epithelial tissues, aldosterone selectivity is determined by 11 beta-hydroxysteroid dehydrogenase type II. In other tissues cortisol is the primary ligand; in some tissues cortisol may act as an antagonist. To better target MR, an understanding of the structural determinants of tissue and ligand-specific MR activation is required. Our focus is on interactions of the ligand-binding domain (LBD) with ligand, the N-terminal domain and putative co-regulatory molecules. Molecular modelling has identified a region in the LBD of the MR and indeed other steroid receptors that critically defines ligand-specificity for aldosterone and cortisol, yet is not part of the ligand-binding pocket. An interaction between the N-terminus and LBD observed in the MR is aldosteronedependent but is unexpectedly antagonised by cortisol. The structural basis of this interaction has been defined. We have identified proteins which interact in the presence of either aldosterone or cortisol but not both. These have been confirmed as coactivators of the full-length hMR. The structural basis of this interaction has been determined for tesmin, a ligand-discriminant coactivator of the MR. The successful identification of the structural basis of antagonism and of ligand-specific interactions of the MR may provide the basis for the development of novel MR ligands with tissue specificity. (C) 2015 Elsevier Ireland Ltd. All rights reserved.