Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism.

ABSTRACT: Steroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-?⁴ structure, such as testosterone or progesterone, are catalyzed by steroid 5?-reductases (SRD5As) to generate their corresponding 3-oxo-5? steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A from Proteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0?Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-?⁴ reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.

SUBMITTER: Han Y 

PROVIDER: S-EPMC7815742 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature