1equ
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(New page: 200px<br /> <applet load="1equ" size="450" color="white" frame="true" align="right" spinBox="true" caption="1equ, resolution 3.00Å" /> '''TYPE 1 17-BETA HYDR...)
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Revision as of 14:39, 12 November 2007
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TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EQUILIN COMPLEXED WITH NADP+
Overview
Excess 17beta-estradiol (E2), the most potent of human estrogens, is known, to act as a stimulus for the growth of breast tumors. Human estrogenic, 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which catalyzes, the reduction of inactive estrone (E1) to the active 17beta-estradiol in, breast tissues, is a key enzyme responsible for elevated levels of E2 in, breast tumor tissues. We present here the structure of the ternary complex, of 17beta-HSD1 with the cofactor NADP+ and, 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin), an equine estrogen used, in estrogen replacement therapy. The ternary complex has been crystallized, with a homodimer, the active form of the enzyme, in the asymmetric unit., Structural and kinetic data presented here show that the, 17beta-HSD1-catalyzed reduction of E1 to E2 in vitro is specifically, inhibited by equilin. The crystal structure determined at 3.0-A resolution, reveals that the equilin molecule is bound at the active site in a mode, similar to the binding of substrate. The orientation of the 17-keto group, with respect to the nicotinamide ring of NADP+ and catalytic residues, Tyr-155 and Ser-142 is different from that of E2 in the 17beta-HSD1-E2, complex. The ligand and substrate-entry loop densities are well defined in, one subunit. The substrate-entry loop adopts a closed conformation in this, subunit. The result demonstrates that binding of equilin at the active, site of 17beta-HSD1 is the basis for inhibition of E1-to-E2 reduction by, this equine estrogen in vitro. One possible outcome of estrogen, replacement therapy in vivo could be reduction of E2 levels in breast, tissues and hence the reduced risk of estrogen-dependent breast cancer.
About this Structure
1EQU is a Single protein structure of sequence from Homo sapiens with NAP and EQI as ligands. Active as Estradiol 17-beta-dehydrogenase, with EC number 1.1.1.62 Full crystallographic information is available from OCA.
Reference
Structure of the ternary complex of human 17beta-hydroxysteroid dehydrogenase type 1 with 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin) and NADP+., Sawicki MW, Erman M, Puranen T, Vihko P, Ghosh D, Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):840-5. PMID:9927655
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