Structure of Human Steroid 5α-Reductase 2 with the Anti-Androgen Drug Finasteride

The paper reports the crystal structure of human steroid 5α-reductase 2 (SRD5A2) with the anti-androgen drug finasteride, providing molecular insights into the catalytic mechanism of SRD5A2, the irreversible action of finasteride on SRD5A2, and the molecular mechanisms underlying the pathological effects of disease-associated mutations. The study reveals unexpected structural features for the binding of NADP+/NADPH and steroid substrates, and the steroid substrates likely access the ligand-binding pocket of SRD5A2 from the lipid bilayer through the opening between TM1 and TM4. The study also suggests that human SRD5A2 and bacterial MaSR1 can be aligned on their core structure of six transmembrane helices that participate in the binding of NADPH and substrates.