Hormones, structure-function correlation

The author and a co-worker later exploited 3 mm NMR probe capabilities in a study of the thermal degradation products of the oxazolidinone antibiotic Zyvox (linezolid, 41) based on the use of H-15N heteronuclear shift correlation experiments.127 In a study of the structure-function relationships of a new growth hormone-releasing peptide, ghrelin, Bednarek and co-workers128 at Merck utilized micro-probe capabilities in the characterization of the structures of the minimum sequence of ghrelin necessary for activity. As a result of these efforts, a small spiroindan, MK-0677 (59) with oral bioavailability was found to be one of the most potent synthetic analogs with this activity. 

In addition, the net charge of the hormone could also influence its binding ability. Thus, the observation of conformational patterns among thyroactive structures which correlate with function, activity and binding data provide useful information in describing specific types of hormone-receptor interactions. 

The impacts of contaminants on the structure of the immune system can be assessed by examining white blood cell (WBC) numbers and the mass and cellularity of immune organs, although these indicators are usually not as sensitive as measures of immune function. Avian immunotoxicity studies frequently assess total and (or) differential WBC counts [79], and immunosuppression can be indicated by reduced numbers of WBCs or elevated WBC numbers caused by recurrent infections. An elevated heterophil to lymphocyte ratio can indicate altered immune status in response to corticosteroid stress hormones or other factors [78,7 9], Exposure to lead shot or lead acetate has been shown to alter total and (or) differential WBC numbers in Japanese quail (Coturnix coturnix) and mallards [81-83], In western grebes (Aechmophorus occidentalis) from California, concentrations of mercury in the kidney were positively correlated with heterophil... 

In a very broad overview of the structural categories one can state several statistical correlations with type of function. Hemes are almost always bound by helices, but never in parallel a//3 structures. Relatively complex enzymatic functions, especially those involving allosteric control, are occasionally antiparallel /3 but most often parallel a//3. Binding and receptor proteins are most often antiparallel /3, while the proteins that bind in those receptor sites (i.e., hormones, toxins, and enzyme inhibitors) are most apt to be small disulfide-rich structures. However, there are exceptions to all of the above generalizations (such as cytochrome cs as a nonhelical heme protein or citrate synthase as a helical enzyme), and when one focuses on the really significant level of detail within the active site then the correlation with overall tertiary structure disappears altogether. For almost all of the dozen identifiable groups of functionally similar proteins that are represented by at least two known protein structures, there are at least... 

Analysis of the TBPA-Ti complex (39,40) indicates that the binding site for the hormone is located deep inside the channel. The hormone makes extensive interactions with the protein side chains that project into the channel. The 4 -hydroxyl of Ti interacts with a patch of hydroxy-amino acids of the protein while each of the iodines makes contact with a number of hydro-phobic protein residues. The T amino acid side chain functional groups are in appropriate positions to interact with glutamic acid and lysine residues. Thus, this channel provides a favorable environment for each of the characteristic substituents of the thyroid hormone (40). However, because of the Ti orientation disorder in the protein complex, this structural model is not a sensitive measure of the observed correlations between diphenyl ether conformations and binding affinity data. 

Various methods have been used in attempts to correlate the structure and function of the different cell components. Comparison of the fine structure of cells with differing functions shows that the number of mitochondria is correlated with metabolic activity and that the number of ribosomes relates to protein-synthesizing ability. Cytochemical techniques, including histochemistry, autoradiography and the use of fluorescent antibodies, have also contributed to our knowledge of the localization of particular enzymes, hormones and reactions. While these techniques have their limitations, they possess the great advantage that they cause little disturbance of the cell structure. On the other hand, cell fractionation techniques, which are widely used by biochemists, require the total disruption of cells. This is followed by the isolation and analysis of the released components. 

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