Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy
Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy
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DOI：
10.1126/science.289.5476.119
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发表时间：
2000-07-07
期刊：
影响因子：
56.9
通讯作者：
Lifton, RP
中科院分区：
文献类型：
--
作者：
Geller, DS;Farhi, A;Lifton, RP
高血压和与妊娠有关的高血压是主要的公共卫生问题，其原因基本上不明。我们描述了盐皮质激素受体（MR）S810 L突变，该突变导致早发性高血压，在妊娠期明显加重。这种突变导致组成型MR活性并改变受体特异性，孕酮和其他缺乏21-羟基的类固醇，通常是MR拮抗剂，成为有效的激动剂。结构和生物化学研究表明，突变导致获得螺旋5和螺旋3之间的货车范德华相互作用，其取代了野生型受体中类固醇21-羟基与螺旋3的相互作用。这种螺旋5-螺旋3相互作用在不同的核激素受体中高度保守，表明其在受体活化中的一般作用。
Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.