Targeting specific PDZ domains of PSD-95; structural basis for enhanced affinity and enzymatic stability of a cyclic peptide.

Published

Journal Article

A cyclic peptide, Tyr-Lys-c[-Lys-Thr-Glu(betaAla)-]-Val, incorporating a beta-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 as well as producing a 10-fold enhancement in binding affinity. Additionally, the cyclization greatly enhances the enzymatic stability, increasing the duration that the peptide inhibits the association between PSD-95 and glutamate receptors, effectively inhibiting the clustering of kainate receptors for over 14 hr after application. Highly specific regulation of kainate receptor action may provide a novel route for treatment of drug addiction and epilepsy.

Full Text

Duke Authors

Cited Authors

  • Piserchio, A; Salinas, GD; Li, T; Marshall, J; Spaller, MR; Mierke, DF

Published Date

  • April 2004

Published In

Volume / Issue

  • 11 / 4

Start / End Page

  • 469 - 473

PubMed ID

  • 15123241

Pubmed Central ID

  • 15123241

Electronic International Standard Serial Number (EISSN)

  • 1879-1301

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2004.03.013

Language

  • eng