3HB5

Binary and ternary crystal structures of a novel inhibitor of 17 beta-HSD type 1: a lead compound for breast cancer therapy

Summary for 3HB5

• Entry DOI: 10.2210/pdb3hb5/pdb
• Related: 3HB4
• Descriptor: Estradiol 17-beta-dehydrogenase 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-{[(9beta,14beta,16alpha,17alpha)-3,17-dihydroxyestra-1,3,5(10)-trien-16-yl]methyl}benzamide, ... (4 entities in total)
• Functional Keywords: 17beta-hsd1, cytoplasm, lipid synthesis, nadp, oxidoreductase, polymorphism, steroid biosynthesis
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14061
• Total number of polymer chains: 1
• Total formula weight: 36036.76

Authors

Mazumdar, M.,Lin, S.-X. (deposition date: 2009-05-04, release date: 2009-12-15, Last modification date: 2024-02-21)

Primary citation

Mazumdar, M.,Fournier, D.,Zhu, D.W.,Cadot, C.,Poirier, D.,Lin, S.X.
Binary and ternary crystal structure analyses of a novel inhibitor with 17beta-HSD type 1: a lead compound for breast cancer therapy.
Biochem.J., 424:357-366, 2009

PubMed Abstract: Oestradiol is a well-characterized sex hormone that stimulates breast cancer and other oestrogen-related diseases. 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses the last step in the synthesis of oestradiol and androstenediol in breast tumour tissue. The enzyme's high expression and activity after simultaneous blockade of oestrogen receptors and inhibition of aromatase in the tumour shows the necessity for its inhibition as a requirement for breast cancer therapy. In the present paper, we report structures of the binary and ternary complexes of 17beta-HSD1 with a new inhibitor E2B {3-[3',17'beta-dihydroxyestra-1',3',5'(10')-trien-16'beta-methyl]benzamide}, and the enzyme inhibition by the later. The IC50 value for E2B was determined to be 42 nM in T47D cells. Multiple interactions between E2B and the enzyme include hydrogen bonds and hydrophobic interactions, as well as pi-pi interactions. A kinetic study demonstrated that E2B inhibits the enzyme's reduction forming oestradiol from oestrone, with a Ki of 0.9+/-0.15 nM. Such strong inhibition is in agreement with its extensive interaction with the enzyme, suggesting its potential as a lead compound for breast cancer therapy. In fact, this possibility is enhanced by its capacity for cell penetration similar to natural steroids. Such inhibitors that block oestrogen synthesis to suppress the sulfatase pathway producing oestradiol can be used in adjuvant therapies with oestrogen receptor blockade, opening a new orientation of breast cancer treatment.

PubMed: 19929851
DOI: 10.1042/BJ20091020

Experimental method

X-RAY DIFFRACTION (2 Å)