Structural Basis for the Catalysis and Inhibition of Human Steroid 5α-Reductase 2

The study provides new insights into the structure and function of human steroid 5α-reductases (SRD5As), specifically SRD5A2, an enzyme that converts testosterone to dihydrotestosterone. Mutations in the SRD5A2 gene have been associated with 5α-reductase deficiency and prostate cancer. The drugs finasteride and dutasteride, which inhibit SRD5A2, are used to treat benign prostate hyperplasia and androgenic alopecia, and have also been indicated for COVID-19 treatment. The researchers solved a crystal structure of human SRD5A2 at 2.8 Å with finasteride, revealing a unique structural topology of 7-transmembrane helices and an intermediate adduct of finasteride and NADPH. The study also identified molecular mechanisms for the 5α-reduction of testosterone and the semi-irreversible finasteride inhibition involving residues E57 and Y91 of SRD5A2. These findings could facilitate drug development.