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Document Page 206 interaction between alanine-157 and leucine-165, which are about 3.8 Å apart. Phenylalanine-160 is 4 Å from glycine-164. There also is a hydrogen bond between cysteine-156 and serine-168, which are 3.2 Å apart. This is an interesting structural property of residues in the segment between the conserved tyrosine and lysine residues: this segment is important in stabilizing dimers. This pattern is repeated in the other 11β- and 17β-hydroxysteroid dehydrogenases suggesting conservation of this stabilizing structure, although the residues are not as well conserved as the tyrosine and lysine. K. Human 17β-HSD-2 Figure 6b shows the modeled α helix F interface in human 17β-hydroxysteroid dehydrogenase type 2. Alanine-237 is 3 Å from the hydrophobic part of the side chain of methionine-241 on the other subunit. Methionine-241 is 3.2 Å from serine-234. Alanine-230 is 3.7 Å from phenylalanine-242 and 4.5 Å from valine-245. Alanine-238, the other anchoring residue, is 4.1 Å from alanine-238 on the other subunit. L. Human 17β-HSD-3 Figure 6c shows the modeled α helix F interface in human 17β-hydroxysteroid dehydrogenase-type 3. Alanine-203 is 3.1 Å from alanine-207. Phenylalanine-204 is 3.2 Å from the other phenylalanine-204 and alanine-200. These are the only stabilizing interactions that we find in our analysis. Human 17βhydroxys-teroid dehydrogenase type 3 has the weakest interactions across the α helix F interface among the four types of 17β-hydroxysteroid dehydrogenases. The conformation of this part of 17βhydroxysteroid dehydrogenase type 3 could change upon binding of substrate, leading to other stabilizing interactions. And, of course other parts of the protein may have intersubunit interactions that stabilize the dimer. Alternatively, the hydrophobic surface of α helix F may interact with another protein or a membrane surface, a potentially important regulatory mechanism that we discuss later in this paper. M. Pig 17β-HSD-4 Figure 6d shows the modeled α helix F interface in pig 17β-hydroxysteroid dehydrogenase type 4. Leucine-169 is 2.9 Å from glycine-173. Leucine-174 is 4.3 Å from alanine-162 and 3.3 Å from alanine- 166. There also is a hydrogen bond between serine-165 and serine-175, which are 3 Å apart. N. Prospects for the Application of <strong>Structure</strong>-Function Analysis of Steroid Dehydrogenases in Hormone Therapy In the last two years there has been impressive progress in understanding the structure of steroid dehydrogenases that are important in regulating blood pres http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_206.html [4/5/2004 5:06:25 PM]
Document Page 207 sure and the actions of reproductive hormones. This progress has come from several directions. First, the cloning and sequencing the dehydrogenases that regulate the actions of aldosterone, cortisol, estradiol, and testosterone. Second, determination of the 3D structure of 17β-HSD-1 and several homologs. Analyses of their 3D structures confirm a general principle that structural similarity is much higher than sequence similarity. This supports proposed molecular models of medically important steroid dehydrogenases using the alignment of their sequences onto the templates of 3D structural homologs. Models of 11β-HSD-1 and -2 are beginning to reveal important properties about these enzymes. We now have a good picture of the structural basis for specificity for NADPH and NADH in 11β-HSD-1 and -2. With this information, we can now turn our attention to modeling cortisol in these two enzymes. This information will open up the possibility for developing analogs to regulate the actions of these two enzymes for use in regulating blood pressure and other physiological processes. The development of carbenoxolone, a water-soluble synthetic analog of glycyrrhetinic acid, shows that chemists can create compounds that have high affinity for 11β-HSD. The next task is to synthesize compounds that are specific for 11β-HSD-1 or 11β-HSD-2. Molecular modeling can contribute important information to solving this kind of problem. Similarly important information will come from the 3D models of 17β-HSD-1, -2, -3 and -4. These models will be useful in developing compounds to regulate estrogen and androgen action, which have important application in reproductive medicine and in treating estrogen-dependent breast tumors and androgen-dependent prostatic tumors. Many compounds in plants have estrogenic and androgenic activity; some of these compounds are likely to work via inhibition of one of the 17β-HSD enzymes [27]. Analogous to the development of carbenoxolone to regulate 11β-HSD, we can seek synthetic compounds that regulate specific types of 17β-HSD, which may be useful in reproductive medicine and in treating cancers. Considering the explosive pace of biomedical research and the new developments in computers for sophisticated structural analyses, the next few years promise to yield important advances in design of new hormone therapies <strong>based</strong> on the knowledge of the structure of steroid dehydrogenases. Acknowledgments We thank Drs. Tanaka, Nonaka, Nakanishi, Deyashiki, Hara, and Mitsui for providing us with the x-ray crystallographic coordinates of carbonyl reductase and 7α-hydroxysteroid dehydrogenase. The support of the Supercomputer Center of the University of California, San Diego is gratefully acknowledged. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_207.html [4/5/2004 5:06:27 PM]
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Document [Interleukin-1] homology w
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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