CRYSTAL-STRUCTURES OF A COMPLEXED AND PEPTIDE-FREE MEMBRANE PROTEIN-BINDING DOMAIN - MOLECULAR-BASIS OF PEPTIDE RECOGNITION BY PDZ

Modular PDZ domains, found in many cell junction-associated proteins, mediate the clustering of membrane ion channels by binding to their C- terminus. The X-ray crystallographic structures of the third PDZ domai n from the synaptic protein PSD-95 in complex with and in the absence of its peptide ligand have been determined at 1.8 Angstrom and 2.3 Ang strom resolution, respectively. The structures reveal that a four-resi due C-terminal stretch (X-Thr/Ser-X-Val-COO-) engages the PDZ domain t hrough antiparallel main chain interactions with a beta sheet of the d omain. Recognition of the terminal carboxylate group of the peptide is conferred by a cradle of main chain amides provided by a Gly-Leu-Gly- Phe loop as well as by an arginine side chain. Specific side chain int eractions and a prominent hydrophobic pocket explain the selective rec ognition of the C-terminal consensus sequence.