1afs
From Proteopedia
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'''RECOMBINANT RAT LIVER 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE (3-ALPHA-HSD) COMPLEXED WITH NADP AND TESTOSTERONE''' | '''RECOMBINANT RAT LIVER 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE (3-ALPHA-HSD) COMPLEXED WITH NADP AND TESTOSTERONE''' | ||
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==Reference== | ==Reference== | ||
Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase., Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis M, Structure. 1997 Jun 15;5(6):799-812. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9261071 9261071] | Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase., Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis M, Structure. 1997 Jun 15;5(6):799-812. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9261071 9261071] | ||
| - | [[Category: 3-alpha-hydroxysteroid dehydrogenase (B-specific)]] | ||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: Ma, H.]] | [[Category: Ma, H.]] | ||
[[Category: Penning, T M.]] | [[Category: Penning, T M.]] | ||
| - | [[Category: | + | [[Category: Nad]] |
| - | [[Category: | + | [[Category: Oxidoreductase]] |
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Revision as of 07:12, 2 May 2008
RECOMBINANT RAT LIVER 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE (3-ALPHA-HSD) COMPLEXED WITH NADP AND TESTOSTERONE
Overview
BACKGROUND: Mammalian 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs) modulate the activities of steroid hormones by reversibly reducing their C3 ketone groups. In steroid target tissues, 3 alpha-HSDs act on 5 alpha-dihydrotestosterone, a potent male sex hormone (androgen) implicated in benign prostate hyperplasia and prostate cancer. Rat liver 3 alpha-HSD belongs to the aldo-keto reductase (AKR) superfamily and provides a model for mammalian 3 alpha-, 17 beta- and 20 alpha-HSDs, which share > 65% sequence identity. The determination of the structure of 3 alpha-HSD in complex with NADP+ and testosterone (a competitive inhibitor) will help to further our understanding of steroid recognition and hormone regulation by mammalian HSDs. RESULTS: We have determined the 2.5 A resolution crystal structure of recombinant rat liver 3 alpha-HSD complexed with NADP+ and testosterone. The structure provides the first picture of an HSD ternary complex in the AKR superfamily, and is the only structure to date of testosterone bound to a protein. It reveals that the C3 ketone in testosterone, corresponding to the reactive group in a substrate, is poised above the nicotinamide ring which is involved in hydride transfer. In addition, the C3 ketone forms hydrogen bonds with two active-site residues implicated in catalysis (Tyr55 and His117). CONCLUSIONS: The active-site arrangement observed in the 3 alpha-HSD ternary complex structure suggests that each positional-specific and stereospecific reaction catalyzed by an HSD requires a particular substrate orientation, the general features of which can be predicted. 3 alpha-HSDs are likely to bind substrates in a similar manner to the way in which testosterone is bound in the ternary complex, that is with the A ring of the steroid substrate in the active site and the beta face towards the nicotinamide ring to facilitate hydride transfer. In contrast, we predict that 17 beta-HSDs will bind substrates with the D ring of the steroid in the active site and with the alpha face towards the nicotinamide ring. The ability to bind substrates in only one or a few orientations could determine the positional-specificity and stereospecificity of each HSD. Residues lining the steroid-binding cavities are highly variable and may select these different orientations.
About this Structure
1AFS is a Single protein structure of sequence from Rattus norvegicus. Full crystallographic information is available from OCA.
Reference
Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase., Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis M, Structure. 1997 Jun 15;5(6):799-812. PMID:9261071 Page seeded by OCA on Fri May 2 10:12:38 2008
