4L1X

Crystal Structuer of Human 3-alpha Hydroxysteroid Dehydrogenase Type 3 V54L Mutant in Complex with NADP+ and Progesterone

Summary for 4L1X

• Entry DOI: 10.2210/pdb4l1x/pdb
• Related: 4L1W
• Descriptor: Aldo-keto reductase family 1 member C2, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, PROGESTERONE, ... (5 entities in total)
• Functional Keywords: alpha-beta barrel, human 3-alpha hsd3, akr, akr1c2, oxidoreductase, aldo-keto reductase, nadph
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (Potential): P52895
• Total number of polymer chains: 2
• Total formula weight: 76248.64

Authors

Zhang, B.,Hu, X.-J.,Lin, S.-X. (deposition date: 2013-06-03, release date: 2014-04-16, Last modification date: 2023-11-08)

Primary citation

Zhang, B.,Zhu, D.-W.,Hu, X.-J.,Zhou, M.,Shang, P.,Lin, S.-X.
Human 3-alpha hydroxysteroid dehydrogenase type 3 (3 alpha-HSD3): The V54L mutation restricting the steroid alternative binding and enhancing the 20 alpha-HSD activity
J.Steroid Biochem.Mol.Biol., 141:135-143, 2014

PubMed Abstract: Human 3-alpha hydroxysteroid dehydrogenase type 3 (3α-HSD3) has an essential role in the inactivation of 5α-dihydrotestosterone (DHT). Notably, human 3α-HSD3 shares 97.8% sequence identity with human 20-alpha hydroxysteroid dehydrogenase (20α-HSD) and there is only one amino acid difference (residue 54) that is located in their steroid binding pockets. However, 20α-HSD displays a distinctive ability in transforming progesterone to 20α-hydroxy-progesterone (20α-OHProg). In this study, to understand the role of residue 54 in the steroid binding and discrimination, the V54L mutation in human 3α-HSD3 has been created. We have solved two crystal structures of the 3α-HSD3·NADP(+)·Progesterone complex and the 3α-HSD3 V54L·NADP(+)·progesterone complex. Interestingly, progesterone adopts two different binding modes to form complexes within the wild type enzyme, with one binding mode similar to the orientation of a bile acid (ursodeoxycholate) in the reported ternary complex of human 3α-HSD3·NADP(+)·ursodeoxycholate and the other binding mode resembling the orientation of 20α-OHProg in the ternary complex of human 20α-HSD·NADP(+)·20α-OHProg. However, the V54L mutation directly restricts the steroid binding modes to a unique one, which resembles the orientation of 20α-OHProg within human 20α-HSD. Furthermore, the kinetic study has been carried out. The results show that the V54L mutation significantly decreases the 3α-HSD activity for the reduction of DHT, while this mutation enhances the 20α-HSD activity to convert progesterone.

PubMed: 24434280
DOI: 10.1016/j.jsbmb.2014.01.003

Experimental method

X-RAY DIFFRACTION (2 Å)