1FDT: Human 17-Beta-Hydroxysteroid-Dehydrogenase Type 1 Complexed With Estradiol And Nadp+

BACKGROUND: The steroid hormone 17beta-estradiol is important in the genesis and development of human breast cancer. Its intracellular concentration is regulated by 17beta-hydroxysteroid dehydrogenase, which catalyzes the reversible reduction of estrone to 17beta-estradiol. This enzyme is thus an important target for inhibitor design. The precise localization and orientation of the substrate and cofactor in the active site is of paramount importance for the design of such inhibitors, and for an understanding of the catalytic mechanism. RESULTS: The structure of recombinant human 17beta-hydroxysteroid dehydrogenase of type 1 (17beta-HSD1) in complex with estradiol at room temperature has been determined at 1.7 A resolution, and a ternary 17betaHSD1-estradiol-NADP+ complex at -150 degrees C has been solved and refined at 2.20 A resolution. The structures show that estradiol interacts with the enzyme through three hydrogen bonds (involving side chains of Ser142, Tyr155 and His221), and hydrophobic interactions between the core of the steroid and nine other residues. The NADP+ molecule binds in an extended conformation, with the nicotinamide ring close to the estradiol molecule. CONCLUSIONS: From the structure of the complex of the enzyme with the substrate and cofactor of the oxidation reaction, the orientation of the substrates for the reduction reaction can be deduced with confidence. A triangular hydrogen-bond network between Tyr155, Ser142 and O17 from estradiol probably facilitates the deprotonation of the reactive tyrosine, while the conserved Lys159 appears not to be directly involved in catalysis. Both the steroid-binding site and the NADPH-binding site can be proposed as targets for the design of inhibitors.
PDB ID: 1FDTDownload
MMDB ID: 56115
PDB Deposition Date: 1996/6/28
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 1FDT: dimeric; determined by author and by software (PISA,PQS)
Molecular Components in 1FDT
Label Count Molecule
Proteins (2 molecules)
17-beta-hydroxysteroid-dehydrogenase(Gene symbol: HSD17B1)
Molecule annotation
Chemicals (6 molecules)
* Click molecule labels to explore molecular sequence information.

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