3CV6

The crystal structure of mouse 17-alpha hydroxysteroid dehydrogenase GG225.226PP mutant in complex with inhibitor and cofactor NADP+.

Summary for 3CV6

• Entry DOI: 10.2210/pdb3cv6/pdb
• Descriptor: Aldo-keto reductase family 1 member C21, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[(1R,2S)-1-ethyl-2-(4-hydroxyphenyl)butyl]phenol, ... (5 entities in total)
• Functional Keywords: aldo-keto reductase, hydroxysteroid dehydrogenase, ternary complex, hexestrol, lipid metabolism, nadp, oxidoreductase, phosphoprotein, steroid metabolism
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 76427.62

Authors

Dhagat, U.,El-Kabbani, O. (deposition date: 2008-04-17, release date: 2009-03-03, Last modification date: 2023-11-01)

Primary citation

Dhagat, U.,Endo, S.,Mamiya, H.,Hara, A.,El-Kabbani, O.
Structure of the G225P/G226P mutant of mouse 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) ternary complex: implications for the binding of inhibitor and substrate.
Acta Crystallogr.,Sect.D, 65:257-265, 2009

PubMed Abstract: 3(17)alpha-Hydroxysteroid dehydrogenase (AKR1C21) is a unique member of the aldo-keto reductase (AKR) superfamily owing to its ability to reduce 17-ketosteroids to 17alpha-hydroxysteroids, as opposed to other members of the AKR family, which can only produce 17beta-hydroxysteroids. In this paper, the crystal structure of a double mutant (G225P/G226P) of AKR1C21 in complex with the coenzyme NADP(+) and the inhibitor hexoestrol refined at 2.1 A resolution is presented. Kinetic analysis and molecular-modelling studies of 17alpha- and 17beta-hydroxysteroid substrates in the active site of AKR1C21 suggested that Gly225 and Gly226 play an important role in determining the substrate stereospecificity of the enzyme. Additionally, the G225P/G226P mutation of the enzyme reduced the affinity (K(m)) for both 3alpha- and 17alpha-hydroxysteroid substrates by up to 160-fold, indicating that these residues are critical for the binding of substrates.

PubMed: 19237748
DOI: 10.1107/S0907444908044028

Experimental method

X-RAY DIFFRACTION (2.1 Å)