Phosphodiesterase 6 (PDE6) is a critical enzyme in the eyesight signaling pathway. When activated, PDE6 hydrolyzes cGMP to GMP, which deactivates cGMP-gated ion channels, causing hyperpolarization of the cell and activating the sensory neurons responsible for vision. Within the PDE family, PDE6 is the only enzyme known to have an inhibitory subunit (PDE6-γ), which allows for the regulation of cGMP levels. When PDE6-γ is bound to PDE6, the enzyme is turned “off” and cannot catalyze cGMP.  Mutations in two mobile loops of PDE6 (the H- and M-loops) reduce affinity for PDE6-γ interactions despite the loops being distant from the PDE6-γ binding site. PDE6 has proven problematic to isolate preventing a structure from being solved and therefore a chimera of the structurally similar PDE5 and PDE6 (PDE5/6) has been used experimentally to gain information about PDE6. To study the native sequence of PDE6, a computational approach was applied by creating a homology model of PDE6. Using this model has allowed us to understand the structural basis for PDE6’s inhibition by PDE6-γ. <br/>            We investigate correlations in protein dynamics possibly responsible for allosteric properties by running 1 microsecond of simulations and carrying out various analyses. Systems of the homology model of PDE6, PDE5, and PDE5/6 in Apo, sildenafil bound, and γ bound states were constructed and equilibrium MD simulations were performed. Our analyses were aimed at validating our homology model of PDE6 and showing the affect of sildenafil and PDE6-γ within each system and across different systems. These studies have allowed us to gain insight into the structural characteristics and the specific residues that are involved in allosteric communication and regulation of PDE6’s inhibition by PDE6-γ. Using cross-correlational analyses we have discovered a novel region that shows correlation with the H- and M-loops and could be a potential allostertic site to target to treat conditions such as retinitis pigmentosa.

Computational investigations into the structure and correlated dynamics of PDE6 and its inhibition by PDE6-γ

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.