The primary goal of this project is to achieve a molecular level understanding of the biological and physiological events surrounding steroid synthesis, function and metabolism. A secondary goal is to use this knowledge to facilitate the development of safe, effective drugs for use as steroid agonists and antagonists in controlling fertility, in cancer chemotherapy, and in the treatment of steroid hormone related disorders and deficiencies. In order to obtain the detailed molecular images necessary for the realization of these goals, X-ray crystal structure determinations of hormonal steroids and the proteins with which they interact will be undertaken, and a continuing effort to discover correlations between molecular conformation and biological activity will be made. The proteins to be studied are representative of steroid binding and steroid metabolizing proteins. They include 3Alpha,20Beta-hydroxysteroid dehydrogenase from Streptomyces hydrogenans, 3Beta-hydroxysteroid specific alcohol dehydrogenase, rat liver 3Alpha-hydroxysteroid dehydrogenase, rat prostatic binding protein and guinea pig corticosteroid binding globulin. Maintenance of a complete data bank of all known steroid crystal structures through the NIH/PROPHET computer network will insure dissemination of structural information to the scientific community. As a result of our past efforts to correlate steroid structure with protein binding and hormone action, we have postulated that the A rings of estrogens, progestins, glucocorticoids, and mineralocorticoids play a dominant role in initiating receptor binding while the D rings have primary control over subsequent events associated with hormonal activity. This """"""""A-ring binding/D-ring acting"""""""" model provides a powerful tool for categorizing structural features and contributing to the development of clinically useful hormone agonists and antagonists. During the next five years we will test, extend and exploit the implications of this model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK026546-22
Application #
3483475
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1979-12-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
22
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Hauptman-Woodward Medical Research Institute
Department
Type
DUNS #
074025479
City
Buffalo
State
NY
Country
United States
Zip Code
14203
Huether, Robert; Liu, Zhi-Jie; Xu, Hao et al. (2010) Sequence fingerprint and structural analysis of the SCOR enzyme A3DFK9 from Clostridium thermocellum. Proteins 78:603-13
Huether, Robert; Mao, Qilong; Duax, William L et al. (2010) The short-chain oxidoreductase Q9HYA2 from Pseudomonas aeruginosa PAO1 contains an atypical catalytic center. Protein Sci 19:1097-103
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Mao, Qilong; Duax, William L; Umland, Timothy C (2007) Crystallization and X-ray diffraction analysis of the beta-ketoacyl-acyl carrier protein reductase FabG from Aquifex aeolicus VF5. Acta Crystallogr Sect F Struct Biol Cryst Commun 63:106-9
Sundlov, Jesse A; Garringer, Julie A; Carney, Jill M et al. (2006) Determination of the crystal structure of EntA, a 2,3-dihydro-2,3-dihydroxybenzoic acid dehydrogenase from Escherichia coli. Acta Crystallogr D Biol Crystallogr 62:734-40
Duax, William L; Thomas, James; Pletnev, Vladimir et al. (2005) Determining structure and function of steroid dehydrogenase enzymes by sequence analysis, homology modeling, and rational mutational analysis. Ann N Y Acad Sci 1061:135-48
Pletnev, Vladimir Z; Duax, William L (2005) Rational proteomics IV: modeling the primary function of the mammalian 17beta-hydroxysteroid dehydrogenase type 8. J Steroid Biochem Mol Biol 94:327-35
Thomas, James L; Duax, William L; Addlagatta, Anthony et al. (2004) Structure/function aspects of human 3beta-hydroxysteroid dehydrogenase. Mol Cell Endocrinol 215:73-82
Thomas, James L; Umland, Timothy C; Scaccia, Launa A et al. (2004) The higher affinity of human type 1 3beta-hydroxysteroid dehydrogenase (3beta-HSD1) for substrate and inhibitor steroids relative to human 3beta-HSD2 is validated in MCF-7 tumor cells and related to subunit interactions. Endocr Res 30:935-41
Thomas, James L; Duax, William L; Addlagatta, Anthony et al. (2003) Structure/function relationships responsible for coenzyme specificity and the isomerase activity of human type 1 3 beta-hydroxysteroid dehydrogenase/isomerase. J Biol Chem 278:35483-90

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