Targeting the PDZ domains of molecular scaffolds of transmembrane ion channels
Journal Title: The AAPS Journal - Year 2006, Vol 8, Issue 2
Abstract
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, Zol) 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 necessited 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.
Authors and Affiliations
Andrea Piserchio, Mark Spaller, Dale F. Mierke
Keywords
Related Articles
- EP ID EP681792
- DOI 10.1007/BF02854911
- Views 77
- Downloads 0
Erratum to: Translational Biomarkers: from Preclinical to Clinical a Report of 2009 AAPS/ACCP Biomarker Workshop
The online version of the original article can be found at 10.1208/s12248-011-9265-x.
High-Throughput Biophysical Analysis of Protein Therapeutics to Examine Interrelationships Between Aggregate Formation and Conformational Stability
Stabilization and formulation of therapeutic proteins against physical instability, both structural alterations and aggregation, is particularly challenging not only due to each protein’s unique physicochemical c...
Current industrial practices of assessing permeability and P-glycoprotein interaction
Combination of the in vitro models that are high throughput but less predictive and the in vivo models that are low throughput but more predictive is used effectively to evaluate the intestinal permeability and transport...
Kinetics of hallmark biochemical changes in paclitaxel-induced apoptosis
Apoptosis is associated with cascades of biochemical changes, including caspase activation, cleavage of poly-ADP-ribose polymerase (PARP), and fragmentation of genomic DNA. Knowledge of the kinetics of these changes in d...
Reproductible production of a PEGylated dual-acting peptide for diabetes
A pEGylated glucagon-like peptide-1 (GLP-1) agonist and glucagon antagonist hybrid peptide was engineered as a potential treatment for type 2 diabetes. To support preclinical development of this PEGylated dual-acting pep...