Ischemic heart disease‐associated ∆ <scp>M1</scp> ‐ <scp>Q91 PDE5A2</scp> mutant shows reduced efficacy for <scp>cGMP</scp> , but not sildenafil, binding‐induced conformational change

Phosphodiesterase 5 (PDE5) regulates several physiological processes, including cardiovascular function. A familial PDE5A variant resulting in an N-terminal truncation (∆M1-Q91) in PDE5A2 has been linked to premature ischemic heart disease, but its functional impact is unclear. Using computational analysis and BRET-based biosensors, we show that ∆M1-Q91 deletion alters structural dynamics and reduces the efficacy of cGMP-induced conformational change in PDE5. Molecular dynamics simulations and normal mode analysis using structural models revealed altered dynamics and correlated motions in the mutant. BRET assays showed a higher EC₅₀ for cGMP-induced, but not sildenafil-induced, conformational change in the ∆M1-Q91 mutant PDE5A2. These findings suggest that M1-Q91 deletion impairs cGMP-mediated allosteric regulation in PDE5A2 without altering inhibitor sensitivity, offering insights into potential precision therapies targeting this variant.