Zhang Junhui, Tsai Francis T F, Geller David S
Section of Nephrology, Yale University School of Medicine, PO Box 208029, New Haven, CT 06520-8029, USA.
J Mol Endocrinol. 2006 Aug;37(1):163-73. doi: 10.1677/jme.1.02089.
Steroid hormone receptor antagonists are widely used in clinical medicine, but their use is often complicated by the lack of receptor specificity to presently available drugs. We previously demonstrated an important role of a widely conserved helix 3 (H3)-helix 5 (H5) interaction in determining the sensitivity and specificity of steroid hormone receptors to receptor agonists. Intriguingly, the same H3 residues also play a crucial role in receptor antagonism; mutation of these residues alters the response of these receptors to antagonists. Given the close interaction of H3 and H5 residues at this site, we asked whether H5 residues might also play a role in the sensitivity of these receptors to antagonists. We demonstrate here that modification of H5 residues produces marked changes in the sensitivities of the glucocorticoid and progesterone receptor (PR) to RU486 antagonism. Moreover, while we confirm previous reports that alteration of the H3 residue, Gly 722 prevents RU486-mediated inhibition of the PR, we show that the corresponding substitution in the glucocorticoid receptor does not inhibit RU486-mediated receptor antagonism. Taken together, our data support the notion that RU486 binds differently to these two receptors, providing a potential target for the design of more specific antiglucocorticoid and antiprogestin drugs.
类固醇激素受体拮抗剂在临床医学中广泛应用，但其应用常因目前可用药物缺乏受体特异性而变得复杂。我们之前证明了广泛保守的螺旋3（H3）-螺旋5（H5）相互作用在决定类固醇激素受体对受体激动剂的敏感性和特异性方面的重要作用。有趣的是，相同的H3残基在受体拮抗作用中也起着关键作用；这些残基的突变会改变这些受体对拮抗剂的反应。鉴于该位点H3和H5残基的紧密相互作用，我们询问H5残基是否也可能在这些受体对拮抗剂的敏感性中发挥作用。我们在此证明，H5残基的修饰会使糖皮质激素和孕激素受体（PR）对RU486拮抗作用的敏感性产生显著变化。此外，虽然我们证实了之前的报道，即H3残基Gly 722的改变会阻止RU486介导的PR抑制，但我们表明糖皮质激素受体中的相应替代并不抑制RU486介导的受体拮抗作用。综上所述，我们的数据支持这样一种观点，即RU486与这两种受体的结合方式不同，这为设计更具特异性的抗糖皮质激素和抗孕激素药物提供了一个潜在靶点。
