1ahh: Difference between revisions

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7 ALPHA-HYDROXYSTEROID DEHYDROGENASE COMPLEXED WITH NAD+

OverviewOverview

7 alpha-Hydroxysteroid dehydrogenase (7 alpha-HSDH;1 EC 1.1.1.159) is an NAD+-dependent oxidoreductase belonging to the short-chain dehydrogenase/reductase (SDR) 1 family. It catalyzes the dehydrogenation of a hydroxyl group at position 7 of the steroid skeleton of bile acids. The crystal structure of the binary (complexed with NAD+) complex of 7 alpha-HSDH has been solved at 2.3 A resolution by the multiple isomorphous replacement method. The structure of the ternary complex [the enzyme complexed with NADH, 7-oxoglycochenodeoxycholic acid (as a reaction product), and possibly partially glycochenodeoxycholic acid (as a substrate)] has been determined by a difference Fourier method at 1.8 A resolution. The enzyme 7 alpha-HSDH is an alpha/beta doubly wound protein having a Rossmann-fold domain for NAD (H) binding. Upon substrate binding, large conformation changes occur at the substrate binding loop (between the beta F strand and alpha G helix) and the C-terminal segment (residues 250-255). The variable amino acid sequences of the substrate-binding loop appear to be responsible for the wide variety of substrate specificities observed among the enzymes of the SDR family. The crystal structure of the ternary complex of 7 alpha-HSDH, which is the only structure available as the ternary complex among the enzymes of the SDR family, indicates that the highly conserved Tyr159 and Ser146 residues most probably directly interact with the hydroxyl group of the substrates although this observation cannot be definite due to an insufficiently characterized nature of the ternary complex. The strictly conserved Lys163 is hydrogen-bonded to both the 2'- and 3'-hydroxyl groups of the nicotinamide ribose of NAD(H). We propose a new catalytic mechanism possibly common to all the enzymes belonging to the SDR family in which a tyrosine residue (Tyr159) acts as a catalytic base and a serine residue (Ser146) plays a subsidiary role of stabilizing substrate binding.

About this StructureAbout this Structure

1AHH is a Single protein structure of sequence from Escherichia coli with as ligand. Active as 7-alpha-hydroxysteroid dehydrogenase, with EC number 1.1.1.159 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structures of the binary and ternary complexes of 7 alpha-hydroxysteroid dehydrogenase from Escherichia coli., Tanaka N, Nonaka T, Tanabe T, Yoshimoto T, Tsuru D, Mitsui Y, Biochemistry. 1996 Jun 18;35(24):7715-30. PMID:8672472

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-[[Image:1ahh.gif|left|200px]]<br /><applet load="1ahh" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1ahh.gif|left|200px]]<br /><applet load="1ahh" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1ahh, resolution 2.3&Aring;" />
 '''7 ALPHA-HYDROXYSTEROID DEHYDROGENASE COMPLEXED WITH NAD+'''<br />
 ==Overview==
-alpha-Hydroxysteroid dehydrogenase (7 alpha-HSDH;1 EC 1.1.1.159) is an, NAD+-dependent oxidoreductase belonging to the short-chain, dehydrogenase/reductase (SDR) 1 family. It catalyzes the dehydrogenation, of a hydroxyl group at position 7 of the steroid skeleton of bile acids., The crystal structure of the binary (complexed with NAD+) complex of 7, alpha-HSDH has been solved at 2.3 A resolution by the multiple isomorphous, replacement method. The structure of the ternary complex [the enzyme, complexed with NADH, 7-oxoglycochenodeoxycholic acid (as a reaction, product), and possibly partially glycochenodeoxycholic acid (as a, substrate)] has been determined by a difference Fourier method at 1.8 A, resolution. The enzyme 7 alpha-HSDH is an alpha/beta doubly wound protein, having a Rossmann-fold domain for NAD (H) binding. Upon substrate binding, large conformation changes occur at the substrate binding loop (between, the beta F strand and alpha G helix) and the C-terminal segment (residues, 250-255). The variable amino acid sequences of the substrate-binding loop, appear to be responsible for the wide variety of substrate specificities, observed among the enzymes of the SDR family. The crystal structure of the, ternary complex of 7 alpha-HSDH, which is the only structure available as, the ternary complex among the enzymes of the SDR family, indicates that, the highly conserved Tyr159 and Ser146 residues most probably directly, interact with the hydroxyl group of the substrates although this, observation cannot be definite due to an insufficiently characterized, nature of the ternary complex. The strictly conserved Lys163 is, hydrogen-bonded to both the 2'- and 3'-hydroxyl groups of the nicotinamide, ribose of NAD(H). We propose a new catalytic mechanism possibly common to, all the enzymes belonging to the SDR family in which a tyrosine residue, (Tyr159) acts as a catalytic base and a serine residue (Ser146) plays a, subsidiary role of stabilizing substrate binding.
+alpha-Hydroxysteroid dehydrogenase (7 alpha-HSDH;1 EC 1.1.1.159) is an NAD+-dependent oxidoreductase belonging to the short-chain dehydrogenase/reductase (SDR) 1 family. It catalyzes the dehydrogenation of a hydroxyl group at position 7 of the steroid skeleton of bile acids. The crystal structure of the binary (complexed with NAD+) complex of 7 alpha-HSDH has been solved at 2.3 A resolution by the multiple isomorphous replacement method. The structure of the ternary complex [the enzyme complexed with NADH, 7-oxoglycochenodeoxycholic acid (as a reaction product), and possibly partially glycochenodeoxycholic acid (as a substrate)] has been determined by a difference Fourier method at 1.8 A resolution. The enzyme 7 alpha-HSDH is an alpha/beta doubly wound protein having a Rossmann-fold domain for NAD (H) binding. Upon substrate binding, large conformation changes occur at the substrate binding loop (between the beta F strand and alpha G helix) and the C-terminal segment (residues 250-255). The variable amino acid sequences of the substrate-binding loop appear to be responsible for the wide variety of substrate specificities observed among the enzymes of the SDR family. The crystal structure of the ternary complex of 7 alpha-HSDH, which is the only structure available as the ternary complex among the enzymes of the SDR family, indicates that the highly conserved Tyr159 and Ser146 residues most probably directly interact with the hydroxyl group of the substrates although this observation cannot be definite due to an insufficiently characterized nature of the ternary complex. The strictly conserved Lys163 is hydrogen-bonded to both the 2'- and 3'-hydroxyl groups of the nicotinamide ribose of NAD(H). We propose a new catalytic mechanism possibly common to all the enzymes belonging to the SDR family in which a tyrosine residue (Tyr159) acts as a catalytic base and a serine residue (Ser146) plays a subsidiary role of stabilizing substrate binding.
 ==About this Structure==
-AHH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with NAD as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/7-alpha-hydroxysteroid_dehydrogenase 7-alpha-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.159 1.1.1.159] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1AHH OCA].
+AHH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=NAD:'>NAD</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/7-alpha-hydroxysteroid_dehydrogenase 7-alpha-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.159 1.1.1.159] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1AHH OCA].
 ==Reference==
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 [[Category: short-chain dehydrogenase/reductase]]
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