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1mrq

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[[Image:1mrq.gif|left|200px]]
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{{STRUCTURE_1mrq| PDB=1mrq | SCENE= }}
{{STRUCTURE_1mrq| PDB=1mrq | SCENE= }}
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'''Crystal structure of human 20alpha-HSD in ternary complex with NADP and 20alpha-hydroxy-progesterone'''
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===Crystal structure of human 20alpha-HSD in ternary complex with NADP and 20alpha-hydroxy-progesterone===
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==Overview==
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Human 20alpha-hydroxysteroid dehydrogenase (h20alpha-HSD; AKR1C1) catalyzes the transformation of progesterone (Prog) into 20alpha-hydroxy-progesterone (20alpha-OHProg). Although h20alpha-HSD shares 98% sequence identity with human type 3 3alpha-HSD (h3alpha-HSD3, AKR1C2), these two enzymes differ greatly in their activities. In order to explain these differences, we have solved the crystal structure of h20alpha-HSD in a ternary complex with NADP(+) and 20alpha-OHProg at 1.59A resolution. The steroid is stabilized by numerous hydrophobic interactions and a hydrogen bond between its O20 and the N(epsilon ) atom of His222. This new interaction prevents the formation of a hydrogen bond with the cofactor, as seen in h3alpha-HSD3 ternary complexes. By combining structural, direct mutagenesis and kinetic studies, we found that the H(222)I substitution decreases the K(m) value for the cofactor 95-fold. With these results, we hypothesize that the rotation of the lateral chain of His222 could be a mediating step between the transformation of Prog and the release of the cofactor. Moreover, crystal structure analysis and direct mutagenesis experiments lead us to identify a new residue involved in the binding of Prog. Indeed, the R(304)L substitution leads to a 65-fold decrease in the K(m) value for Prog reduction. We thus propose that Prog is maintained in a new steroid-binding site composed mainly of residues found in the carboxy-terminal region of the protein.
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{{ABSTRACT_PUBMED_12899831}}
==About this Structure==
==About this Structure==
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[[Category: Progesterone]]
[[Category: Progesterone]]
[[Category: Ternary complex]]
[[Category: Ternary complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 01:38:27 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 08:39:01 2008''

Revision as of 05:39, 29 July 2008

Image:1mrq.png

Template:STRUCTURE 1mrq

Crystal structure of human 20alpha-HSD in ternary complex with NADP and 20alpha-hydroxy-progesterone

Template:ABSTRACT PUBMED 12899831

About this Structure

1MRQ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and site-directed mutagenesis studies lead to the identification of an alternative binding site for C21-steroids., Couture JF, Legrand P, Cantin L, Luu-The V, Labrie F, Breton R, J Mol Biol. 2003 Aug 15;331(3):593-604. PMID:12899831

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