1y5r: Difference between revisions

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The crystal structure of murine 11b-hydroxysteroid dehydrogenase complexed with corticosterone

OverviewOverview

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of 11-dehydrocorticosterone to its active form corticosterone in rodents (or cortisone to cortisol in humans). The reductive reaction of the 11-keto to 11-hydroxyl is the pivotal switch in the activation of glucocorticoids. An excess of active glucocorticoids has been shown to play a key role in metabolic disorders such as diabetes and obesity. Therefore, 11beta-HSD1 represents an important therapeutic target for the treatment of these diseases. To facilitate the iterative design of inhibitors, we have crystallized and determined the three-dimensional structures of a binary complex of murine 11beta-HSD1 with NADP(H) to a resolution of 2.3 A and of a ternary complex with corticosterone and NADP(H) to a resolution of 3.0 A by X-ray crystallography. The enzyme forms a homodimer in the crystal and has a fold similar to those of other members of the family of short chain steroid dehydrogenases/reductases (SDRs). The structure shows a novel folding feature at the C-terminus of the enzyme. The C-terminal helix insertions provide additional dimer contacts, exert an influence on the conformations of the substrate binding loops, and present hydrophobic regions for potential membrane attachment. The structure also reveals how 11beta-HSD1 achieves its selectivity for its substrate.

About this StructureAbout this Structure

1Y5R is a Single protein structure of sequence from Mus musculus with and as ligands. Active as 11-beta-hydroxysteroid dehydrogenase, with EC number 1.1.1.146 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of murine 11 beta-hydroxysteroid dehydrogenase 1: an important therapeutic target for diabetes., Zhang J, Osslund TD, Plant MH, Clogston CL, Nybo RE, Xiong F, Delaney JM, Jordan SR, Biochemistry. 2005 May 10;44(18):6948-57. PMID:15865440

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OCA

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-[[Image:1y5r.gif|left|200px]]<br /><applet load="1y5r" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1y5r.gif|left|200px]]<br /><applet load="1y5r" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1y5r, resolution 3.0&Aring;" />
 '''The crystal structure of murine 11b-hydroxysteroid dehydrogenase complexed with corticosterone'''<br />
 ==Overview==
-Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the, conversion of 11-dehydrocorticosterone to its active form corticosterone, in rodents (or cortisone to cortisol in humans). The reductive reaction of, the 11-keto to 11-hydroxyl is the pivotal switch in the activation of, glucocorticoids. An excess of active glucocorticoids has been shown to, play a key role in metabolic disorders such as diabetes and obesity., Therefore, 11beta-HSD1 represents an important therapeutic target for the, treatment of these diseases. To facilitate the iterative design of, inhibitors, we have crystallized and determined the three-dimensional, structures of a binary complex of murine 11beta-HSD1 with NADP(H) to a, resolution of 2.3 A and of a ternary complex with corticosterone and, NADP(H) to a resolution of 3.0 A by X-ray crystallography. The enzyme, forms a homodimer in the crystal and has a fold similar to those of other, members of the family of short chain steroid dehydrogenases/reductases, (SDRs). The structure shows a novel folding feature at the C-terminus of, the enzyme. The C-terminal helix insertions provide additional dimer, contacts, exert an influence on the conformations of the substrate binding, loops, and present hydrophobic regions for potential membrane attachment., The structure also reveals how 11beta-HSD1 achieves its selectivity for, its substrate.
+Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of 11-dehydrocorticosterone to its active form corticosterone in rodents (or cortisone to cortisol in humans). The reductive reaction of the 11-keto to 11-hydroxyl is the pivotal switch in the activation of glucocorticoids. An excess of active glucocorticoids has been shown to play a key role in metabolic disorders such as diabetes and obesity. Therefore, 11beta-HSD1 represents an important therapeutic target for the treatment of these diseases. To facilitate the iterative design of inhibitors, we have crystallized and determined the three-dimensional structures of a binary complex of murine 11beta-HSD1 with NADP(H) to a resolution of 2.3 A and of a ternary complex with corticosterone and NADP(H) to a resolution of 3.0 A by X-ray crystallography. The enzyme forms a homodimer in the crystal and has a fold similar to those of other members of the family of short chain steroid dehydrogenases/reductases (SDRs). The structure shows a novel folding feature at the C-terminus of the enzyme. The C-terminal helix insertions provide additional dimer contacts, exert an influence on the conformations of the substrate binding loops, and present hydrophobic regions for potential membrane attachment. The structure also reveals how 11beta-HSD1 achieves its selectivity for its substrate.
 ==About this Structure==
-Y5R is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with NDP and C0R as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/11-beta-hydroxysteroid_dehydrogenase 11-beta-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.146 1.1.1.146] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Y5R OCA].
+Y5R is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=NDP:'>NDP</scene> and <scene name='pdbligand=C0R:'>C0R</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/11-beta-hydroxysteroid_dehydrogenase 11-beta-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.146 1.1.1.146] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y5R OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Mus musculus]]
 [[Category: Single protein]]
-[[Category: Clogston, C.L.]]
+[[Category: Clogston, C L.]]
-[[Category: Delaney, J.M.]]
+[[Category: Delaney, J M.]]
 [[Category: Jordan, S.]]
-[[Category: Nybo, R.E.]]
+[[Category: Nybo, R E.]]
-[[Category: Osslund, T.D.]]
+[[Category: Osslund, T D.]]
-[[Category: Plant, M.H.]]
+[[Category: Plant, M H.]]
 [[Category: Xiong, F.]]
 [[Category: Zhang, J.]]
@@ Line 26: / Line 26: @@
 [[Category: corticosterone bound]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 06:35:16 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:02:01 2008''