A Look Into The Off-Target Protein That Mistakenly Harbors Erectile Dysfunction Drugs

Humans perceive vision via a specialized tissue at the back of our eye known as the retina. The retina is comprised of highly differentiated and elongated neurons stacked together to perform their function, which is the perception of light. Out of these neurons, rod photoreceptors mediate low-light vision, while cone photoreceptors perceive color vision. Both rod and cone photoreceptors are equipped with exquisite machinery and components necessary for visual phototransduction. Among the visual phototransduction proteins, phosphodiesterase 6 (PDE6) is an essential enzyme that hydrolyzes cyclic guanosine monophosphate (cGMP) in response to light. The reduction in cGMP concentration results in the closure of ion channels in the photoreceptor, leading to human vision.

Rod photoreceptor PDE6 is an atypical member of the phosphodiesterase family (PDEs), comprised of twelve members (PDE1-12). Because of their association with various diseases, PDEs are targets of several widely-used drugs and remain a major target for drug development. However, most drugs have been designed based on their catalytic domains that share high similarity among the PDE family members. As a result, most PDE inhibitors display a high degree of cross-reactivity within the PDE family. For example, PDE5 inhibitors such as sildenafil (Viagra) and vardenafil (Levitra) have multi-billion-dollar drugs that are widely used for the treatment of erectile dysfunction and pulmonary hypertension. But, PDE5 inhibitors have also been associated with several visual side effects, including blurred vision, changes in color vision, extreme sensitivity to light, and, in extreme cases, damage to the optic nerve that relays optical signals to the brain. These side effects are caused by the binding of PDE5 inhibitors to PDE6 in the retina.


In this study, we have determined the structure of the full-length PDE6 using single-particle cryo-electron microscopy. The high-resolution structure of PDE6, an enzyme with great medical and basic scientific interest in vision and beyond, underscores the immense hidden beauty of human vision. The structure of PDE6 reveals several features that were previously unseen, including how the regulatory domains of PDE6 control the activity of its catalytic domain.

The study provides evidence on the reorganization of fish-hook-like regions (known as the GAF β1-β2 loop regions) that form potential signal transduction routes from the regulatory domains of PDE to its catalytic domain. The role of these fish-hook-like regions in controlling PDE activity makes them an interesting target site where a new class of PDE inhibitors can bind and inhibit PDE activity.

In summary, the discovery of these signal-relaying hooks might provide a solid framework for designing selective molecules that can lessen the side effects caused by cross-reactivity of PDE inhibitors.

These findings are described in the article entitled Cryo-EM structure of phosphodiesterase 6 reveals insights into the allosteric regulation of type I phosphodiesterases, recently published in the journal Science Advances.


Further reading:




Study On How Resilience Affects Stress And Alcohol-Related Behaviors In National Guard Members

Our recent study is the first to show how stressors are related to serious consequences of alcohol use in military […]

How To Calculate A Percentage

You can calculate a percentage easily by just using a few different tricks, the most common way is to divide […]

Computational Tools And OR For Optimal Design Of Cogeneration Systems

The search for fast, secure, and reliable solutions intensifies the use of computational tools to support the decision-making process and, […]

Genome-Wide Association Studies For Coronary Artery Disease Risk

Human disease can be loosely categorized into two broad categories, monogenic and polygenic diseases. The word monogenic means mutating a […]

Using Double-Frequency Ground Penetrating Radar To Measure Ice Accumulation

In cold regions, ice accumulation often affects navigation, flood control, water supply, power generation, and other human activities. Under extreme […]

Designing Better Lithium-ion Batteries  

With the increase in world population and quality living, energy has become a significant part of our daily life. Currently, […]

Fossil Beetles From Cretaceous Amber Show New Insights Into Early Plant-Insect Relationships

Coleoptera, commonly known as “beetles,” with about 400,000 species, is the largest order in nature, constituting almost 40% of described […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?