From Proteopedia
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| - | [[Image:1mrq.gif|left|200px]] | + | {{Seed}} |
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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'''
| + | ===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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12899831}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12899831 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_12899831}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Progesterone]] | | [[Category: Progesterone]] |
| | [[Category: Ternary complex]] | | [[Category: Ternary complex]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 01:38:27 2008'' | + | |
| | + | ''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
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
Page seeded by OCA on Tue Jul 29 08:39:01 2008
