Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, USA.
Steroids. 2011 Dec 11;76(13):1451-7. doi: 10.1016/j.steroids.2011.07.015. Epub 2011 Aug 5.
The serum of Atlantic sea lamprey, a basal vertebrate, contains two corticosteroids, 11-deoxycortisol and deoxycorticosterone. Only 11-deoxycortisol has high affinity [K(d) ~ 3 nM] for the corticoid receptor [CR] in lamprey gill cytosol. To investigate the binding of 11-deoxycortisol to the CR, we constructed 3D models of lamprey CR complexed with 11-deoxycortisol and deoxycorticosterone. These 3D models reveal that Leu-220 and Met-299 in lamprey CR have contacts with the 17α-hydroxyl on 11-deoxycortisol. Lamprey CR is the ancestor of the mineralocorticoid receptor [MR] and glucocorticoid receptor [GR]. Unlike human MR and human GR, the 3D model of lamprey CR finds a van der Waals contact between Cys-227 in helix 3 and Met-264 in helix 5. Mutant human MR and GR containing a van der Waals contact between helix 3 and helix 5 display enhanced responses to progesterone and glucocorticoids, respectively. We propose that this interaction was present in the CR and lost during the evolution of the MR and GR, leading to changes in their response to progesterone and corticosteroids, respectively.
大西洋七鳃鳗的血清中含有两种皮质甾醇，11-脱氧皮质醇和脱氧皮质酮。只有 11-脱氧皮质醇对七鳃鳗鳃细胞溶质中的皮质甾醇受体（CR）具有高亲和力[K(d)~3 nM]。为了研究 11-脱氧皮质醇与 CR 的结合，我们构建了与 11-脱氧皮质醇和脱氧皮质酮结合的七鳃鳗 CR 的 3D 模型。这些 3D 模型表明，七鳃鳗 CR 中的亮氨酸 220 和蛋氨酸 299 与 11-脱氧皮质醇的 17α-羟基有接触。七鳃鳗 CR 是盐皮质激素受体（MR）和糖皮质激素受体（GR）的祖先。与人类 MR 和人类 GR 不同，七鳃鳗 CR 的 3D 模型发现第 3 螺旋中的半胱氨酸 227 和第 5 螺旋中的蛋氨酸 264 之间存在范德华接触。含有第 3 螺旋和第 5 螺旋之间范德华接触的突变型人类 MR 和 GR 分别对孕酮和糖皮质激素表现出增强的反应。我们提出，这种相互作用存在于 CR 中，并在 MR 和 GR 的进化过程中丢失，导致它们对孕酮和皮质甾醇的反应分别发生变化。
