FIGURE 10-23 Two Zn2+ fingers of the glucocorticoid receptor. Single-letter abbreviations of the amino acids are used. Functional aspects of amino acid residues are indicated. AA 457-462 represent critical amino acids in the P box that generate binding specificity to the response element. AA 477-481 represent the D box involved in the recognition of spacing between half-sites of the response element and dimerization. Reproduced with permission from Luisi, B. F., Schwabe, J. W. R., and Freedman, L. P. (1994). The steroid/ nuclear receptors: from three-dimensional structure to complex function. Vitam. Horm., 49:1-48.

steroidal ligand binds to the receptor in this form, the complex is triggered to dissociate, so that free receptor monomer is formed. This process has been referred to as cytoplasmic activation or transformation. The receptor becomes hyperphosphorylated. The "activated" receptor can enter the nucleopore as a monomer or as a homodimer and be transported to the nucleoplasm, where it searches DNA until the hormone-responsive element is encountered. There it binds tightly to DNA as a homodimer and probably binds DNA into a configuration that is preferred for the entry of the other transactivating proteins that comprise the transcriptional complex. In the case of mouse mammary tumor virus LTR, the transactivating proteins of the transcriptional complex are shown in Figure 10-25. A cartoon of the retinoic acid receptor-retinoic acid X receptor heterodimer facilitates a view of how these proteins could assemble in a transcriptional complex (Figure 10-26). Once racheted in place, RNA polymerase II is able to start transcribing the open reading frame of the activated gene. Eventually, the steroid-receptor complex dissociates from the DNA and is transported back into the cytoplasm after a dephosphorylation event takes place. In some tissues, for example, the liver, the dissociated steroid is quickly metabolized to an inactive form. The liberated receptor becomes phosphorylated and reassembled into the inactive oligomeric state. Some of the receptor may be degraded rather than entering the reassembly process. The reassembled oligomer is now poised for another event in which glucocorticoid ligand is released from the adrenal gland.

A hypothetical model of the steroid receptor-binding domain has been developed by analogy with the structures inherent in certain protease enzymes. This model is shown in Figure 10-27. For the glucocorti coid receptor, the steroid would enter the binding pocket A ring first, and two potential conflicts with the A ring are indicated. Part way toward the mouth of the binding pocket, a point of attachment is seen with the C-ll substituent on the C ring. Then closer to the mouth of the pocket, two interactions with the D ring are indicated. Although not proven, models like these will stimulate further research that will help to arrive at the actual structure of the steroid-binding domain.

Cure Tennis Elbow Without Surgery

Cure Tennis Elbow Without Surgery

Everything you wanted to know about. How To Cure Tennis Elbow. Are you an athlete who suffers from tennis elbow? Contrary to popular opinion, most people who suffer from tennis elbow do not even play tennis. They get this condition, which is a torn tendon in the elbow, from the strain of using the same motions with the arm, repeatedly. If you have tennis elbow, you understand how the pain can disrupt your day.

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