Targeting Specific PDZ Domains of PSD-95: Structural Basis for Enhanced Affinity and Enzymatic Stability of a Cyclic Peptide dayong

A cyclic peptide, Tyr-Lys-c[-Lys-Thr-Glu(βAla)-]-Val, incorporating a β-Ala lactam side chain linker and designed to target the PDZ domains of the postsynaptic density protein 95 (PSD-95), has been synthesized and structurally characterized by NMR while free and bound to the PDZ1 domain of PSD-95. While bound, the lactam linker of the peptide makes a number of unique contacts outside the canonical PDZ binding motif, providing a novel target for PDZ-domain specificity …

…Investigator Award Lecture. Structures of larger proteins, protein-ligand and protein-DNA complexes by multidimensional heteronuclear NMR. Protein Sci. 3, 372-390. [Medline] Sattler, M., Schleucher, J., and Griesinger, C. (1999). Heteronuclear multidimensional NMR experiments for the structure determination of proteins in solution employing pulsed field gradients. Prog. NMR Spec. 34, 93-158. [Medline] Vuister, G.W. and Bax, A. (1994). Measurement of four-bond HN-H alpha J-couplings in staphylococcal nuclease. J. Biomol. NMR 4, 193-200. [Medline] Received: November 21, 2003 Revised: January 8, 2004 Accepted: January 8, 2004 Published: April 16, 2004