Xray Crystallography And Steroid Fit At The Receptor

The x-ray structures have now been solved for the ligand-binding domains of all the steroid hormone receptors (ERa and ER3,18-20 PR,21 AR,22 GR,23'24 and MR25). The x-ray crystal structures of the ER, PR, and AR have revealed a key difference that leads to the unique ligand specificity of the ERs.19,26 In the region of the ligand-binding domain, where the A ring of steroids binds, are key residues that bind to either the phenolic A ring of estrogens or the enone A ring of progesterone or testosterone. In the case of the ER, glutamate and arginine residues are important in a hydrogen-bonding network that involves the phenolic hydroxyl. In contrast to this structural arrangement, the PR and AR have glutamine and arginine residues that hydrogen bond to the A-ring enones of progesterone and testosterone. The change from glutamate, a hydrogen-bond acceptor, to glutamine, a hydrogen-bond donor, is critical for the discrimination between estrogens and other steroid hormones. The structures of the GR and MR LBDs also reveal the features that provide the specificities for these two receptors. In the LBD of the GR, key proline and glutamine residues are replaced by serine and leucine, respectively, in the MR.25 The proline residue results in a slightly more open-binding pocket, which can accommodate larger residues at the 17a-position, as seen in many GR ligands, and the glutamine side chain can hydrogen bond with the 17a-hydroxyl, which is seen in GRs, but is absent in aldosterone.

The x-ray crystal structures of the steroid hormones themselves have also provided important information. Although the conformations of rigid molecules in crystals and their preferred conformations in solution with receptors can differ, it is now clear from x-ray crystallography studies of steroids, prostaglandins, thyroid compounds, and many other drug classes that this technique can be a powerful tool in understanding drug action and in designing new drugs.27-29 The relationship is straightforward: steroid drugs usually do not have a charge and, as a result, are held to their receptors by relatively weak forces of attraction. The same is true for steroid molecules as they "pack" into crystals. In both events, the binding energy is too small to hold any but low-energy conformations. In short, the steroid conformation observed in steroid crystals is often the same or very similar to that at the receptor.

Structure of Steroid Hormone-Receptor Complexes

Steroid hormone-receptor complexes include the steroid hormone receptor as well as other proteins, predominantly chaperone (heat shock) proteins, cochaperones, and im-munophilins (Fig. 25.7).30,31 Their role is to "chaperone" the correct conformation and folding of complex proteins, which is otherwise much more difficult as temperatures increase. At normal physiological temperatures, the chaperone proteins assist the proper folding of large proteins such as steroid hormone receptors. The individual components vary depending on the type of steroid hormone receptor. Without the chaperones, the steroid hormone-binding site on the receptor does not have the proper folding and conformation for optimal steroid binding.

Once the steroid hormone binds to the receptor, a con-formational change of the receptor occurs, and the mature receptor complex dissociates (Fig. 25.7). The receptor is dimerized, phosphorylated, and transported into the nucleus, if necessary. There, the zinc fingers on the steroid hormone receptor bind to the target gene(s) in the DNA.

Additional proteins are recruited to the receptor-DNA complex prior to initiation or repression of transcription.32 These additional proteins include coactivators or corepres-sors and histone acetyltransferases. Typically, the recep-tor-DNA-coactivator complex displays histone acetyl-transferase action, which relaxes the chromatin structure, allowing binding of RNA polymerase II and the subsequent initiation of transcription. If corepressors are recruited to the complex, deacetylation of the histone complex is facilitated, preventing transcription.

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