X‑ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity

To better understand the structural
origins of inhibitor selectivity
of human phosphodieasterase families (PDEs 1–11), here we report
the X-ray crystal structure of PDE2 in complex with a highly selective,
nanomolar inhibitor (BAY60-7550) at 1.9 Å resolution, and the
structure of apo PDE2 at 2.0 Å resolution. The crystal structures
reveal that the inhibitor binds to the PDE2 active site by using not
only the conserved glutamine-switch mechanism for substrate binding,
but also a binding-induced, hydrophobic pocket that was not reported
previously. In silico affinity profiling by molecular
docking indicates that the inhibitor binding to this pocket contributes
significantly to the binding affinity and thereby improves the inhibitor
selectivity for PDE2. Our results highlight a structure-based design
strategy that exploits the potential binding-induced pockets to achieve
higher selectivity in the PDE inhibitor development.