Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the [gamma]-subunit
The inhibitory interaction of phosphodiesterase-6 (PDE6) with its {gamma}-subunit (P{gamma}) is pivotal in vertebrate phototransduction. Here, crystal structures of a chimaeric PDE5/PDE6 catalytic domain (PDE5/6cd) complexed with sildenafil or 3-isobutyl-1-methylxanthine and the P{gamma}-inhibitory peptide P{gamma}{sub 70-87} have been determined at 2.9 and 3.0 {angstrom}, respectively. These structures show the determinants and the mechanism of the PDE6 inhibition by P{gamma} and suggest the conformational change of P{gamma} on transducin activation. Two variable H- and M-loops of PDE5/6cd form a distinct interface that contributes to the P{gamma}-binding site. This allows the P{gamma} C-terminus to fit into the opening of the catalytic pocket, blocking cGMP access to the active site. Our analysis suggests that disruption of the H-M loop interface and P{gamma}-binding site is a molecular cause of retinal degeneration in atrd3 mice. Comparison of the two PDE5/6cd structures shows an overlap between the sildenafil and P{gamma}{sub 70-87}-binding sites, thereby providing critical insights into the side effects of PDE5 inhibitors on vision.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1006108
- Journal Information:
- EMBO J., Vol. 28, Issue (22) ; 2009; ISSN 0261-4189
- Country of Publication:
- United States
- Language:
- ENGLISH
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