X‑ray Crystal Structure of Phosphodiesterase
2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals
a Binding-Induced Pocket Important for Selectivity
- Publication date
- Publisher
Abstract
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. <i>In silico</i> 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