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.