Mammalian phosphodiesterase 5 (PDE5) is an enzyme that acts on the cGMP signaling pathway. It catalyzes the hydrolysis of the second messenger cGMP, thus terminating its signal. Due to its role in regulating many cellular functions, PDE5 has been targeted by inhibitor design, such as sildenafil, for the treatment of several clinical conditions including erectile dysfunction and pulmonary arterial hypertension. These PDE5 inhibitors interact differently with the catalytic domain of the enzyme with different selectivities.
This seminar will discuss the regulation of PDE5 activity, including allosteric regulation through cGMP binding to the regulatory GAFa domain in the protein. Specifically, how statistical analysis of protein sequences combined with precision Bioluminescence Resonance Energy Transfer-based molecular biosensors are used to determine and elucidate the role of key coevolving residues in PDE5 GAFa domain.
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