Nahoum Virginie, Gangloff Anne, Shi Rong, Lin Sheng-Xiang
Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Laval University, Québec, Québec G1V 4G2, Canada.
FASEB J. 2003 Jul;17(10):1334-6. doi: 10.1096/fj.02-0524fje. Epub 2003 May 20.
Steroid hormones play an essential role in a wide range of physiological and pathological processes, such as growth, metabolism, aging, and hormone-sensitive cancers. Estrogens are no exception and influence growth, differentiation, and functioning of many target tissues, such as the mammary gland, uterus, hypothalamus, pituitary, bone, and liver. Although very similar in structure, each steroid class (i.e., estrogens, androgens, progestins, mineral corticoids, or glucocorticoids) is responsible for distinct physiological processes. To permit specific biological responses for a given steroid class, specific proteins are responsible for steroid bioactivation, action, and inactivation, yet they have low or no affinity to other classes. Estrogens make no exception and possess their own set of related proteins. To understand the molecular basis underlying estrogen recognition from other steroids, structural features of estrogen-specific proteins were analyzed along with their ability to discriminate between steroid hormones belonging to different classes. Hence, the study of all estrogen-specific proteins for which an atomic structure has been determined demonstrated that a common steroid-binding pocket architecture is shared by these proteins. This architecture is composed of the following elements: i) a glutamate residue acting as a proton acceptor coupled with a proton donor that interact with the steroid O3; ii) a proton donor (His or Ser) that interacts with O17; iii) a highly conserved sandwich-like structure providing steric hindrance and preventing C19 steroid from binding; and iv) several amino acid residues interacting with the C18. As these different estrogen-specific proteins are not related in overall sequence, the inference is that the steroid binding site in these proteins has originated by convergent evolution.
类固醇激素在广泛的生理和病理过程中发挥着重要作用，如生长、代谢、衰老以及激素敏感性癌症。雌激素也不例外，它影响许多靶组织的生长、分化和功能，如乳腺、子宫、下丘脑、垂体、骨骼和肝脏。尽管结构非常相似，但每一类类固醇（即雌激素、雄激素、孕激素、盐皮质激素或糖皮质激素）都负责不同的生理过程。为了使特定类固醇类别产生特定的生物学反应，特定的蛋白质负责类固醇的生物激活、作用和失活，然而它们对其他类别类固醇的亲和力较低或没有亲和力。雌激素也不例外，它有自己的一套相关蛋白质。为了理解雌激素与其他类固醇识别的分子基础，分析了雌激素特异性蛋白质的结构特征及其区分不同类别类固醇激素的能力。因此，对所有已确定原子结构的雌激素特异性蛋白质的研究表明，这些蛋白质共享一个共同的类固醇结合口袋结构。该结构由以下元素组成：i）一个作为质子受体的谷氨酸残基与一个与类固醇O3相互作用的质子供体相连；ii）一个与O17相互作用的质子供体（组氨酸或丝氨酸）；iii）一个高度保守的三明治样结构，提供空间位阻并阻止C19类固醇结合；iv）几个与C18相互作用的氨基酸残基。由于这些不同的雌激素特异性蛋白质在整体序列上不相关，可以推断这些蛋白质中的类固醇结合位点是通过趋同进化产生的。
