1XF0

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) complexed with delta4-androstene-3,17-dione and NADP

Summary for 1XF0

• Entry DOI: 10.2210/pdb1xf0/pdb
• Related: 1RY0 1RY8 1S1P 1S1R 1S2A 1S2C
• Descriptor: Aldo-keto reductase family 1 member C3, ACETATE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: alpha/beta barrel, beta-hairpin, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P42330
• Total number of polymer chains: 1
• Total formula weight: 37985.07

Authors

Qiu, W.,Zhou, M.,Labrie, F.,Lin, S.-X. (deposition date: 2004-09-13, release date: 2004-10-26, Last modification date: 2023-08-23)

Primary citation

Qiu, W.,Zhou, M.,Labrie, F.,Lin, S.-X.
Crystal structures of the multispecific 17beta-hydroxysteroid dehydrogenase type 5: critical androgen regulation in human peripheral tissues
Mol.Endocrinol., 18:1798-1807, 2004

PubMed Abstract: Human type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD5;AKR1C3) plays a major role in the metabolism of androgens in peripheral tissues. In prostate basal cells, this enzyme is involved in the transformation of dehydroepiandrosterone into dihydrotestosterone, the most potent androgen. It is thus a potential target for prostate cancer therapy because it is understood that the testosterone formation by this enzyme is an important factor, particularly in patients who have undergone surgical or medical castration. Here we report the first structure of a human type 5 17beta-HSD in two ternary complexes, in which we found that the androstenedione molecule has a different binding position from that of testosterone. The two testosterone-binding orientations in the substrate-binding site demonstrate the structural basis of the alternative binding and multispecificity of the enzyme. Phe306 and Trp227 are the key residues involved in ligand recognition as well as product release. A safety belt in the cofactor-binding site enhances nicotinamide adenine dinucleotide phosphate binding and accounts for its high affinity as demonstrated by kinetic studies. These structures have provided a dynamic view of the enzyme reaction converting androstenedione to testosterone as well as valuable information for the development of potent enzyme inhibitors.

PubMed: 15087468
DOI: 10.1210/me.2004-0032

Experimental method

X-RAY DIFFRACTION (2 Å)