1JTV

Crystal structure of 17beta-Hydroxysteroid Dehydrogenase Type 1 complexed with Testosterone

Summary for 1JTV

• Entry DOI: 10.2210/pdb1jtv/pdb
• Related: 1IOL
• Descriptor: 17 beta-hydroxysteroid dehydrogenase type 1, TESTOSTERONE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: steroid hormones, alternative binding mode, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14061
• Total number of polymer chains: 1
• Total formula weight: 35268.35

Authors

Shi, R.,Nahoum, V.,Lin, S.X. (deposition date: 2001-08-22, release date: 2003-06-24, Last modification date: 2023-08-16)

Primary citation

Gangloff, A.,Shi, R.,Nahoum, V.,Lin, S.X.
Pseudo-symmetry of C19 steroids, alternative binding orientations, and multispecificity in human estrogenic 17beta-hydroxysteroid dehydrogenase.
FASEB J., 17:274-276, 2003

PubMed Abstract: Steroids are implicated in many physiological processes, such as reproduction, aging, metabolism, and cancer. To understand the molecular basis for steroid recognition and discrimination, we studied the human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) responsible for the last step in the bioactivation of all estrogens. Here we report the first observation of the conversion of dihydrotestosterone (DHT) into 3beta,17beta-androstanediol (3beta-diol) by 17beta-HSD1, an estrogenic enzyme studied for more than half a century. Kinetic observations demonstrate that both the 3beta-reduction of DHT into 3beta-diol (kcat = 0.040 s(-1)1; Km = 32 +/- 9 microM) and the 17beta-oxidation of DHT into androstandione (A-dione) (kcat = 0.19 s(-1); Km = 26 +/-6 microM) are catalyzed by 17beta-HSD1 via alternative binding orientation of the steroid. The reduction of DHT was also observed in intact cells by using HEK-293 cells stably transformed with 17beta-HSD1. The high-resolution structure of a 17beta-HSD1-C19-steroid (testosterone) complex solved at 1.54 A demonstrates that the steroid is reversibly oriented in the active site, which strongly supports the existence of alternative binding mode. Such a phenomenon can be explained by the pseudo-symmetric structure of C19-steroids. Our results confirm the role of the Leu149 residue in C18/C19-steroid discrimination and suggest a possible mechanism of 17beta-HSD1 in the modulation of DHT levels in tissues, such as the breast, where both the enzyme and DHT are present.

PubMed: 12490543

Experimental method

X-RAY DIFFRACTION (1.54 Å)