Imagine trying to fix a car without any idea of what the engine’s components look like. This mirrors a challenge for scientists studying the molecular basis of disease. Without the structural blueprints of biological molecules, it’s difficult to understand how they function in the body, and importantly, where to aim treatments when something goes wrong.
One of these mysteries is the structure of steroid 5α-reductase 2, or SRD5A2, an enzyme central to men’s health. SRD5A2 functions by converting the hormone testosterone to its more potent form, dihydrotestosterone. Disruptions to this process have been linked to conditions from male pattern baldness to prostate cancer. However, the enzyme’s topography and molecular mechanism have eluded structural biologists, limiting the search for more effective drugs to regulate its activity.
In a study published in Nature Communications, researchers at A*STAR’s Bioinformatics Institute (BII) teamed up with collaborators in China and the US to final crack the code. Using a combination of X-ray crystallography and computational techniques for protein structure prediction, they generated the first three-dimensional structural model of SRD5A2.
The researchers also revealed the mechanics behind how this complex enzyme works through a series of molecular docking and molecular dynamics simulations. Human SRD5A2 has a large binding pocket, which remains obscure in its inactive state, said Hao Fan, co-corresponding author on the study and Principal Investigator at BII. Helper molecules called co-factors first need to attach to this binding pocket for the enzymatic reaction to proceed.
“Simulation studies suggest that dynamic loops on the cytosol end act as ‘gates’ that allow specific co-factors access to the catalytic site,” explained Fan, adding that in the closed position, these ‘gates’ hold co-factors in place during the reaction.
The team also used these simulations to demonstrate how finasteride, the SRD5A2 inhibitor commonly prescribed to treat prostate enlargement, blocks SRD5A2 activity by obstructing co-factors from binding to the catalytic site.
“Our study is the first to report a structure of a eukaryotic integral membrane steroid reductase,” said Fan, who plans to use these data as stepping stones towards understanding how SRD5A2 mutations trigger diseases such as prostate cancer. Additionally, Fan and colleagues plan to take a closer look at the SRD5A2 active site to design novel, more potent drugs to tune circulating testosterone levels.
The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute (BII).
