3DOP

Crystal structure of 5beta-reductase (AKR1D1) in complex with NADP+ and 5beta-dihydrotestosterone, Resolution 2.00A

Summary for 3DOP

• Entry DOI: 10.2210/pdb3dop/pdb
• Related: 3CMF
• Descriptor: 3-oxo-5-beta-steroid 4-dehydrogenase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-beta-DIHYDROTESTOSTERONE, ... (4 entities in total)
• Functional Keywords: product, bile acid catabolism, cytoplasm, disease mutation, intrahepatic cholestasis, lipid metabolism, nadp, oxidoreductase, steroid metabolism
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P51857
• Total number of polymer chains: 2
• Total formula weight: 80975.77

Authors

Di Costanzo, L.,Drury, J.E.,Penning, T.M.,Christianson, D.W. (deposition date: 2008-07-05, release date: 2008-10-28, Last modification date: 2023-11-01)

Primary citation

Di Costanzo, L.,Drury, J.E.,Christianson, D.W.,Penning, T.M.
Structure and catalytic mechanism of human steroid 5beta-reductase (AKR1D1)
Mol.Cell.Endocrinol., 301:191-198, 2009

PubMed Abstract: Human steroid 5beta-reductase (aldo-keto reductase (AKR) 1D1) catalyzes reduction of Delta(4)-ene double bonds in steroid hormones and bile acid precursors. We have reported the structures of an AKR1D1-NADP(+) binary complex, and AKR1D1-NADP(+)-cortisone, AKR1D1-NADP(+)-progesterone and AKR1D1-NADP(+)-testosterone ternary complexes at high resolutions. Recently, structures of AKR1D1-NADP(+)-5beta-dihydroprogesterone complexes showed that the product is bound unproductively. Two quite different mechanisms of steroid double bond reduction have since been proposed. However, site-directed mutagenesis supports only one mechanism. In this mechanism, the 4-pro-R hydride is transferred from the re-face of the nicotinamide ring to C5 of the steroid substrate. E120, a unique substitution in the AKR catalytic tetrad, permits a deeper penetration of the steroid substrate into the active site to promote optimal reactant positioning. It participates with Y58 to create a "superacidic" oxyanion hole for polarization of the C3 ketone. A role for K87 in the proton relay proposed using the AKR1D1-NADP(+)-5beta-dihydroprogesterone structure is not supported.

PubMed: 18848863
DOI: 10.1016/j.mce.2008.09.013

Experimental method

X-RAY DIFFRACTION (2 Å)