PDZ domains contain ~80-90 residues that fold into a structure with a b-sandwich of 5-6 b-strands and two a-helices. The peptide ligand binds in a hydrophobic cleft composed of a b-strand (bB), an a-helix and a loop that binds the peptide carboxylate group. The peptide binds in an anti-parallel fashion to the bB strand, with the C-terminal residue occupying a hydrophobic pocket.  PDZ heterodimers form a linear head-to-tail arrangement that involves recognition of an internal on one of the partner proteins. The figure shows the 3rd PDZ domain of PSD-95 bound to a TKNYKQTSV peptide.

 

Domain binding and function

type 1 PDZ consensus binding motif:

x-[ST]-x-F-stop (where F is large and hydrophobic) [Reference: Hung AY, Sheng M (2002) PDZ domains: structural modules for ptoein complex assembly. J. Biol. Chem. 277,  5699-5702]

 

PDZ domains bind to the C-terminal 4-5 residues of their target proteins, frequently transmembrane receptors or ion channels. Reference: Kornau et al. (1995) Domain interactions between NMDA receptor subunits and the postdynaptic density protien PSD-95. Science 269, 1737-1740. 

These interactions can be of high affinity (nM Kd). The consensus binding sequence contains a hydrophobic residue, commonly Val or Ile, at the very C-terminus. Residues at the -2 and -3 positions are important in determining specificity. PDZ domains can also heterodimerize with PDZ domains of different proteins, potentially regulating intracellular signalling. 

Binding examples

PDZ domain protein	Binding partner	Binding Site
Post-synaptic Density protein 95 (PSD-95)	NMDA receptor B via PDZ1 and PDZ2 of PSD-95	IESDV-COOH
	Kvl1.4 (Shaker-type K+ channel) via PDZ1 and PDZ2 of PSD-95	VETDV-COOH
	neural Nitric Oxide Synthase (nNOS) via PDZ2	PDZ/PDZ interaction