Abstract
Human estrogenic 17
β-hydroxysteroid dehydrogenase (17
β-HSD1, EC1.1.1.62) is an important enzyme that catalyses the last step of active estrogen formation. 17
β-HSD1 plays a key role in the proliferation of breast cancer cells. The three-dimensional structures of this enzyme and of the enzyme-estradiol complex have been solved (Zhu et al., 1993, J. Mol. Biol. 234:242; Ghosh et al., 1995, Structure 3:503; Azzi et al., 1996, Nature Struct. Biol. 3:665). The determination of the non-reactive ternary complex structure, which could mimic the transition state, constitutes a further critical step toward the rational design of inhibitors for this enzyme (Ghosh et al. 1995, Structure 3:503; Penning, 1996, Endocrine-Related Cancer, 3:41).
To further study the transition state, two non-reactive ternary complexes, 17
β-HSD1–EM519-NADP
+ and 17
β-HSD1–EM553-NADP
+ were crystallized using combined methods of soaking and co-crystallization. Although they belong to the same C2 space group, they have different unit cells, with
a=155.59 Å,
b=42.82 Å,
c=121.15 Å,
β=128.5° for 17
β-HSD1–EM519-NADP
+, and
a=124.01 Å,
b=45.16 Å,
c=61.40 Å,
β=99.2° for 17
β-HSD1–EM553-NADP
+, respectively. Our preliminary results revealed that the inhibitors interact differently with the enzyme than do the natural substrates.