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| | {{STRUCTURE_1afs| PDB=1afs | SCENE= }} | | {{STRUCTURE_1afs| PDB=1afs | SCENE= }} |
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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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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_9261071}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 9261071 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_9261071}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Nad]] | | [[Category: Nad]] |
| | [[Category: Oxidoreductase]] | | [[Category: Oxidoreductase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 10:12:38 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 16:45:26 2008'' |
Revision as of 13:45, 30 June 2008
Template:STRUCTURE 1afs
RECOMBINANT RAT LIVER 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE (3-ALPHA-HSD) COMPLEXED WITH NADP AND TESTOSTERONE
Template:ABSTRACT PUBMED 9261071
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 Mon Jun 30 16:45:26 2008
