Allosteric binding of cGMP to PDE5 regulatory domain increases affinity of the catalytic site for cGMP, thereby stimulating the rate of cGMP hydrolysis (Thomas et al 1990b; Mullershausen et al 2001; Okada and Asakawa 2002; Corbin et al 2003; Rybalkin et al 2003). cGMP binding to the regulatory domain also stimulates phosphorylation of PDE5 by cGMP-dependent protein kinase (Thomas et al 1990b; Wyatt et al 1998; Mullershausen et al 2001; Murthy 2001; Rybalkin et al 2002b). cGMP binding to these sites must be preceded by occupation of the catalytic site by cGMP (Francis et al 1980; Thomas et al 1990b) and it appears that cGMP binding to the regulatory domain produces a conformational change in PDE5 that exposes Ser-92 allowing phosphorylation which increases affinity of the regulatory domain for cGMP and increases catalytic activity as well (Corbin et al 2000).
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