Sasson S
Department of Pharmacology, Hebrew University School of Medicine, Jerusalem, Israel.
Pathol Biol (Paris). 1991 Jan;39(1):59-69.
The equilibrium binding kinetics of the interaction between the estrogen receptor and natural estrogens (estradiol, estriol and estrone), non-steroidal estrogen agonists (11 beta-chloromethyl-estradiol-17 beta, diethyl-stilbestrol, hexestrol) and non-steroidal antiestrogens (clomiphene, tamoxifen) have been characterized. It is proposed that positive cooperative binding of ligands by the estrogen receptor reflects conformational changes in the DNA binding domain of the receptor dimer which increase its affinity to estrogen responsive elements. Weak estrogens fail to induce maximal cooperativity and are less efficient in activating the receptor complex. Antiestrogens, that inhibit the [3H]estradiol-induced cooperative binding, suppress the activation of the receptor and inhibit its nuclear interactions. Another class of antiestrogens (e.g., 4-hydroxytamoxifen) interacts with the receptor in a manner that is indistinguishable from the cooperative interaction of estradiol, and the resulting complex may also exhibit increased affinity for estrogen responsive elements. However, these complexes cannot activate transcription, presumably due to an aberrant induction of transcription-activating domain in the receptor. We suggest that the positive cooperativity of the estrogen receptor results from conformational changes in the receptor that are transmitted also to the DNA binding domain. On the other hand, conformational changes in the transcription activating domain are not revealed by equilibrium binding kinetics. Thus, compounds that block the positive cooperative binding of [3H]estradiol by the receptor act as antiestrogens. Other compounds that interact cooperatively with the receptor can activate the receptor DNA binding domain, however, they may or may not induce the full array of conformational changes required for transactivation of transcription.
已对雌激素受体与天然雌激素（雌二醇、雌三醇和雌酮）、非甾体雌激素激动剂（11β - 氯甲基 - 雌二醇 - 17β、己烯雌酚、己烷雌酚）以及非甾体抗雌激素（氯米芬、他莫昔芬）之间相互作用的平衡结合动力学进行了表征。有人提出，雌激素受体对配体的正向协同结合反映了受体二聚体DNA结合结构域的构象变化，这种变化增加了其对雌激素反应元件的亲和力。弱雌激素无法诱导最大协同性，且在激活受体复合物方面效率较低。抑制[³H]雌二醇诱导的协同结合的抗雌激素会抑制受体的激活并抑制其核相互作用。另一类抗雌激素（如4 - 羟基他莫昔芬）与受体的相互作用方式与雌二醇的协同相互作用难以区分，并且形成的复合物对雌激素反应元件可能也表现出增加的亲和力。然而，这些复合物无法激活转录，可能是由于受体中转录激活结构域的异常诱导。我们认为雌激素受体的正向协同性源于受体的构象变化，这种变化也传递到了DNA结合结构域。另一方面，转录激活结构域的构象变化在平衡结合动力学中未体现出来。因此，阻断受体对[³H]雌二醇正向协同结合的化合物可作为抗雌激素。其他与受体协同相互作用的化合物可激活受体的DNA结合结构域，然而，它们可能会也可能不会诱导转录激活所需的全部构象变化。
