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Submitted on January 26, 2004
Accepted on April 7, 2004
Oncology and Molecular Endocrinology Research Center, CHUL Medical Center (CHUQ) and Laval University, Quebec, G1V 4G2, Canada
* To whom correspondence should be addressed. E-mail: sxlin{at}crchul.ulaval.ca.
Human type 5 17
-hydroxysteroid dehydrogenase (17-HSD5) plays a major role in the metabolism of androgens in peripheral tissues. In prostate basal cells, this enzyme is involved in the transformation of dehydroepiandrosterone into dihydrotestosterone, the most potent androgen. It is thus a potential target for prostate cancer therapy as it is understood that the testosterone formation by this enzyme is an important factor, particularly in patients who have undergone surgical or medical castration. Here we report the first structure of a human type 5 17-HSD in two ternary complexes, in which we found that the androstenedione molecule has a different binding position from that of testosterone. The two testosterone-binding orientations in the substrate-binding site demonstrate the structural basis of the alternative binding and multi-specificity of the enzyme. Phe306 and Trp227 are the key residues involved in ligand recognition as well as product release. A "safety belt" in the cofactor-binding site enhances NADP binding and accounts for its high affinity as demonstrated by kinetic studies. These structures have provided a dynamic view of the enzyme reaction converting androstenedione to testosterone as well as valuable information for the development of potent enzyme inhibitors.
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