1jtv
From Proteopedia
(New page: 200px<br /> <applet load="1jtv" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jtv, resolution 1.54Å" /> '''Crystal structure o...) |
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caption="1jtv, resolution 1.54Å" /> | caption="1jtv, resolution 1.54Å" /> | ||
'''Crystal structure of 17beta-Hydroxysteroid Dehydrogenase Type 1 complexed with Testosterone'''<br /> | '''Crystal structure of 17beta-Hydroxysteroid Dehydrogenase Type 1 complexed with Testosterone'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Steroids are implicated in many physiological processes, such as | + | Steroids are implicated in many physiological processes, such as reproduction, aging, metabolism, and cancer. To understand the molecular basis for steroid recognition and discrimination, we studied the human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) responsible for the last step in the bioactivation of all estrogens. Here we report the first observation of the conversion of dihydrotestosterone (DHT) into 3beta,17beta-androstanediol (3beta-diol) by 17beta-HSD1, an estrogenic enzyme studied for more than half a century. Kinetic observations demonstrate that both the 3beta-reduction of DHT into 3beta-diol (kcat = 0.040 s(-1)1; Km = 32 +/- 9 microM) and the 17beta-oxidation of DHT into androstandione (A-dione) (kcat = 0.19 s(-1); Km = 26 +/-6 microM) are catalyzed by 17beta-HSD1 via alternative binding orientation of the steroid. The reduction of DHT was also observed in intact cells by using HEK-293 cells stably transformed with 17beta-HSD1. The high-resolution structure of a 17beta-HSD1-C19-steroid (testosterone) complex solved at 1.54 A demonstrates that the steroid is reversibly oriented in the active site, which strongly supports the existence of alternative binding mode. Such a phenomenon can be explained by the pseudo-symmetric structure of C19-steroids. Our results confirm the role of the Leu149 residue in C18/C19-steroid discrimination and suggest a possible mechanism of 17beta-HSD1 in the modulation of DHT levels in tissues, such as the breast, where both the enzyme and DHT are present. |
==About this Structure== | ==About this Structure== | ||
| - | 1JTV 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 TES and GOL 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:// | + | 1JTV 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=TES:'>TES</scene> and <scene name='pdbligand=GOL:'>GOL</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=1JTV OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Lin, S | + | [[Category: Lin, S X.]] |
[[Category: Nahoum, V.]] | [[Category: Nahoum, V.]] | ||
[[Category: Shi, R.]] | [[Category: Shi, R.]] | ||
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[[Category: steroid hormones]] | [[Category: steroid hormones]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:26:39 2008'' |
Revision as of 11:26, 21 February 2008
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Crystal structure of 17beta-Hydroxysteroid Dehydrogenase Type 1 complexed with Testosterone
Overview
Steroids are implicated in many physiological processes, such as reproduction, aging, metabolism, and cancer. To understand the molecular basis for steroid recognition and discrimination, we studied the human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) responsible for the last step in the bioactivation of all estrogens. Here we report the first observation of the conversion of dihydrotestosterone (DHT) into 3beta,17beta-androstanediol (3beta-diol) by 17beta-HSD1, an estrogenic enzyme studied for more than half a century. Kinetic observations demonstrate that both the 3beta-reduction of DHT into 3beta-diol (kcat = 0.040 s(-1)1; Km = 32 +/- 9 microM) and the 17beta-oxidation of DHT into androstandione (A-dione) (kcat = 0.19 s(-1); Km = 26 +/-6 microM) are catalyzed by 17beta-HSD1 via alternative binding orientation of the steroid. The reduction of DHT was also observed in intact cells by using HEK-293 cells stably transformed with 17beta-HSD1. The high-resolution structure of a 17beta-HSD1-C19-steroid (testosterone) complex solved at 1.54 A demonstrates that the steroid is reversibly oriented in the active site, which strongly supports the existence of alternative binding mode. Such a phenomenon can be explained by the pseudo-symmetric structure of C19-steroids. Our results confirm the role of the Leu149 residue in C18/C19-steroid discrimination and suggest a possible mechanism of 17beta-HSD1 in the modulation of DHT levels in tissues, such as the breast, where both the enzyme and DHT are present.
About this Structure
1JTV 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
Pseudo-symmetry of C19 steroids, alternative binding orientations, and multispecificity in human estrogenic 17beta-hydroxysteroid dehydrogenase., Gangloff A, Shi R, Nahoum V, Lin SX, FASEB J. 2003 Feb;17(2):274-6. Epub 2002 Dec 17. PMID:12490543
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