1equ
From Proteopedia
(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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| - | [[Image:1equ.gif|left|200px]]<br /> | + | [[Image:1equ.gif|left|200px]]<br /><applet load="1equ" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1equ" size=" | + | |
caption="1equ, resolution 3.00Å" /> | caption="1equ, resolution 3.00Å" /> | ||
'''TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EQUILIN COMPLEXED WITH NADP+'''<br /> | '''TYPE 1 17-BETA HYDROXYSTEROID DEHYDROGENASE EQUILIN COMPLEXED WITH NADP+'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Excess 17beta-estradiol (E2), the most potent of human estrogens, is known | + | 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== | ==About this Structure== | ||
| - | 1EQU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAP and EQI as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Estradiol_17-beta-dehydrogenase Estradiol 17-beta-dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.62 1.1.1.62] Full crystallographic information is available from [http:// | + | 1EQU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=EQI:'>EQI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Estradiol_17-beta-dehydrogenase Estradiol 17-beta-dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.62 1.1.1.62] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EQU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Ghosh, D.]] | [[Category: Ghosh, D.]] | ||
[[Category: Puranen, T.]] | [[Category: Puranen, T.]] | ||
| - | [[Category: Sawicki, M | + | [[Category: Sawicki, M W.]] |
[[Category: Vihko, P.]] | [[Category: Vihko, P.]] | ||
[[Category: EQI]] | [[Category: EQI]] | ||
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[[Category: short chain dehydrogenase]] | [[Category: short chain dehydrogenase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:30:34 2008'' |
Revision as of 10:30, 21 February 2008
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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 and 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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