The drug sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been approved by the U.S. Food and Drug Administration to treat erectile dysfunction and pulmonary arterial hypertension, and may be advantageous in the future for the treatment of other diseases. However, adverse side effects to vision have been reported. Recently, I solved the crystal structure of the chimeric catalytic domain of the visual effector protein phosphodiesterase 6 (PDE6) with sildenafil bound. A chimera of PDE5 and PDE6 has been created to study the functional and structural properties of PDE6 because PDE6 cannot be functionally expressed efficiently. I hypothesize that sildenafil and the inhibitory gamma-subunit of PDE6 interact at the catalytic site of PDE6 and that these interactions are critical for understanding the mechanisms of the drug effects of vision. My aim is to solve the crystal structure of the chimeric PDE5/6 catalytic domain in complex with sildenafil and the PDE6 gamma-subunit by X-ray crystallography. This structure will allow for the side effects of sildenafil on vision to be closely examined and could potentially lead to the development of more specific PDE5 inhibitors with no visual side effects.
|Program type||Predoctoral Fellowship|
|Effective start/end date||07/01/2008 → 05/31/2009|