Targeting the PDZ domains of molecular scaffolds of transmembrane ion channels.

The family of multidomain proteins known as the synaptic associated proteins (SAPs) act as molecular scaffolds, playing an important role in the signaling and maintenance of several receptors and channels. The SAPs consist of 5 individual protein domains: 3 PDZ (PSD95, Disc Large, Zo1) domains, an SH3 domain, and an inactive guanyl kinase (GK) domain. The 3 PDZ domains bind the C-termini of specific receptors and channels, leading to the transient association with cytoskeletal and signaling proteins. Molecules targeting specific domains of the SAPs may provide a novel route for the regulation of channel and receptor function. Here we describe a structural-based approach for the development of such inhibitors for the PDZ domains of SAP90. The high sequence homology of the 3 domains has necessitated targeting regions outside the canonical binding pocket. The structural features of the PDZ domains with the C-termini of different receptors (GluR6), channels (Kv1.4), and cytoskeletal proteins (CRIPT) provide insight into targeting these regions.