A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor
A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor
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DOI：
10.1074/jbc.m504098200
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发表时间：
2005-09-02
影响因子：
4.8
通讯作者：
Williams, SP
中科院分区：
文献类型：
--
作者：
Bledsoe, RK;Madauss, KP;Williams, SP
配体结合是激素调节盐皮质激素受体（MR）活性的第一步。在这里，我们报告MR（NR 3C 2）结合激动剂和拮抗剂的多个晶体结构。这些结构结合诱变研究表明，最大的受体激活涉及一个复杂的配体介导的氢键网络与Asn（770），它具有双重作用：稳定环之前的C-末端激活功能-2螺旋和直接接触的激素配体。此外，大多数活化配体与螺旋10上的Thr（945）形成氢键。天然存在的S810 L突变体的结构表征解释了螺旋3/螺旋5相互作用的稳定性如何可以规避对这种氢键网络的要求。总而言之，这些结果解释了醛固酮激活MR的效力、孕激素和降压药安体舒通诱导的弱激活以及皮质醇相对于可的松的结合选择性。
Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, wereport multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn(770) which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr(945) on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone.