1FDU

HUMAN 17-BETA-HYDROXYSTEROID-DEHYDROGENASE TYPE 1 MUTANT H221L COMPLEXED WITH ESTRADIOL AND NADP+

Summary for 1FDU

• Entry DOI: 10.2210/pdb1fdu/pdb
• Descriptor: 17-BETA-HYDROXYSTEROID DEHYDROGENASE, SULFATE ION, ESTRADIOL, ... (5 entities in total)
• Functional Keywords: dehydrogenase, 17-beta-hydroxysteroid, mutant, estradiol, nadp
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14061
• Total number of polymer chains: 4
• Total formula weight: 144243.24

Authors

Mazza, C.,Breton, R.,Housset, D.,Fontecilla-Camps, J.-C. (deposition date: 1998-01-14, release date: 1998-05-27, Last modification date: 2024-05-22)

Primary citation

Mazza, C.,Breton, R.,Housset, D.,Fontecilla-Camps, J.C.
Unusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenase.
J.Biol.Chem., 273:8145-8152, 1998

PubMed Abstract: 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.

PubMed: 9525918
DOI: 10.1074/jbc.273.14.8145

Experimental method

X-RAY DIFFRACTION (2.7 Å)