Targeting specific PDZ domains of PSD-95; structural basis for enhanced affinity and enzymatic stability of a cyclic peptide.
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.
Piserchio
Andrea
A
Department of Chemistry, Division of Biology & Medicine, Brown University, Providence, RI 02912 USA.
Salinas
Gregory D
GD
Li
Tao
T
Marshall
John
J
Spaller
Mark R
MR
Mierke
Dale F
DF
D004795:Enzyme Stability / Q000502:physiology; D008024:Ligands; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D008024:Ligands; D009419:Nerve Tissue Proteins; D010456:Peptides, Cyclic; D018092:Kainic Acid Receptors; C033652:postsynaptic density proteins