3hb5

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

spinqualitylabelsall models 3hb5, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3hb5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: E2B, NAP Related: 3hb4 Activity: 17-beta-estradiol 17-dehydrogenase, with EC number 1.1.1.62 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DHB1_HUMAN] Favors the reduction of estrogens and androgens. Also has 20-alpha-HSD activity. Uses preferentially NADH. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Binary and ternary crystal structure analyses of a novel inhibitor with 17beta-HSD type 1: a lead compound for breast cancer therapy.,Mazumdar M, Fournier D, Zhu DW, Cadot C, Poirier D, Lin SX Biochem J. 2009 Dec 10;424(3):357-66. PMID:19929851 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hydroxysteroid dehydrogenase 3D structures

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