1fdw: Difference between revisions

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==Overview==

Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the, short chain dehydrogenase reductase (SDR) family, is responsible for the, synthesis of 17beta-estradiol, the biologically active estrogen involved, in the genesis and development of human breast cancers. Here, we report, the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+, and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol, complexes. These structures provide a complete picture of the NADP+-enzyme, interactions involving the flexible 191-199 loop (well ordered in the, H221L mutant) and suggest that the hydrophobic residues Phe192-Met193, could facilitate hydride transfer. 17beta-HSD1 appears to be unique among, the members of the SDR protein family in that one of the two basic, residues involved in the charge compensation of the 2'-phosphate does not, belong to the Rossmann-fold motif. The remarkable stabilization of the, NADP+ 2'-phosphate by the enzyme also clearly establishes its preference, for this cofactor relative to NAD+. Analysis of the catalytic properties, of, and estradiol binding to, the two mutants suggests that the, His221-steroid O3 hydrogen bond plays an important role in substrate, specificity.

Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short chain dehydrogenase reductase (SDR) family, is responsible for the synthesis of 17beta-estradiol, the biologically active estrogen involved in the genesis and development of human breast cancers. Here, we report the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+ and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol complexes. These structures provide a complete picture of the NADP+-enzyme interactions involving the flexible 191-199 loop (well ordered in the H221L mutant) and suggest that the hydrophobic residues Phe192-Met193 could facilitate hydride transfer. 17beta-HSD1 appears to be unique among the members of the SDR protein family in that one of the two basic residues involved in the charge compensation of the 2'-phosphate does not belong to the Rossmann-fold motif. The remarkable stabilization of the NADP+ 2'-phosphate by the enzyme also clearly establishes its preference for this cofactor relative to NAD+. Analysis of the catalytic properties of, and estradiol binding to, the two mutants suggests that the His221-steroid O3 hydrogen bond plays an important role in substrate specificity.

==About this Structure==

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[[Category: Single protein]]

[[Category: Breton, R.]]

[[Category: Fontecilla-Camps, J.C.]]

[[Category: Fontecilla-Camps, J C.]]

[[Category: Housset, D.]]

[[Category: Mazza, C.]]

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[[Category: nadp]]

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@@ Line 4: / Line 4: @@
 ==Overview==
-Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the, short chain dehydrogenase reductase (SDR) family, is responsible for the, synthesis of 17beta-estradiol, the biologically active estrogen involved, in the genesis and development of human breast cancers. Here, we report, the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+, and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol, complexes. These structures provide a complete picture of the NADP+-enzyme, interactions involving the flexible 191-199 loop (well ordered in the, H221L mutant) and suggest that the hydrophobic residues Phe192-Met193, could facilitate hydride transfer. 17beta-HSD1 appears to be unique among, the members of the SDR protein family in that one of the two basic, residues involved in the charge compensation of the 2'-phosphate does not, belong to the Rossmann-fold motif. The remarkable stabilization of the, NADP+ 2'-phosphate by the enzyme also clearly establishes its preference, for this cofactor relative to NAD+. Analysis of the catalytic properties, of, and estradiol binding to, the two mutants suggests that the, His221-steroid O3 hydrogen bond plays an important role in substrate, specificity.
+Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short chain dehydrogenase reductase (SDR) family, is responsible for the synthesis of 17beta-estradiol, the biologically active estrogen involved in the genesis and development of human breast cancers. Here, we report the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+ and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol complexes. These structures provide a complete picture of the NADP+-enzyme interactions involving the flexible 191-199 loop (well ordered in the H221L mutant) and suggest that the hydrophobic residues Phe192-Met193 could facilitate hydride transfer. 17beta-HSD1 appears to be unique among the members of the SDR protein family in that one of the two basic residues involved in the charge compensation of the 2'-phosphate does not belong to the Rossmann-fold motif. The remarkable stabilization of the NADP+ 2'-phosphate by the enzyme also clearly establishes its preference for this cofactor relative to NAD+. Analysis of the catalytic properties of, and estradiol binding to, the two mutants suggests that the His221-steroid O3 hydrogen bond plays an important role in substrate specificity.
 ==About this Structure==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Breton, R.]]
-[[Category: Fontecilla-Camps, J.C.]]
+[[Category: Fontecilla-Camps, J C.]]
 [[Category: Housset, D.]]
 [[Category: Mazza, C.]]
@@ Line 25: / Line 25: @@
 [[Category: nadp]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 09:39:46 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:37:40 2008''