1rgr

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Cyclic Peptides Targeting PDZ Domains of PSD-95: Structural Basis for Enhanced Affinity and Enzymatic Stability

Structural highlights

1rgr is a 2 chain structure with sequence from Rattus norvegicus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR, 22 models
Ligands:BAL
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DLG4_RAT Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B.[1] [2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Targeting specific PDZ domains of PSD-95; structural basis for enhanced affinity and enzymatic stability of a cyclic peptide.,Piserchio A, Salinas GD, Li T, Marshall J, Spaller MR, Mierke DF Chem Biol. 2004 Apr;11(4):469-73. PMID:15123241[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
8 reviews cite this structure
Emerging Themes in PDZ Domain Signaling: Structure, Function, and Inhibition.
Liu et al. (2019)
7 more
32 other articles
No citations found

See Also

References

  1. ↑ Hruska-Hageman AM, Benson CJ, Leonard AS, Price MP, Welsh MJ. PSD-95 and Lin-7b interact with acid-sensing ion channel-3 and have opposite effects on H+- gated current. J Biol Chem. 2004 Nov 5;279(45):46962-8. Epub 2004 Aug 17. PMID:15317815 doi:10.1074/jbc.M405874200
  2. ↑ Prange O, Wong TP, Gerrow K, Wang YT, El-Husseini A. A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13915-20. Epub 2004 Sep 9. PMID:15358863 doi:10.1073/pnas.0405939101
  3. ↑ Piserchio A, Salinas GD, Li T, Marshall J, Spaller MR, Mierke DF. Targeting specific PDZ domains of PSD-95; structural basis for enhanced affinity and enzymatic stability of a cyclic peptide. Chem Biol. 2004 Apr;11(4):469-73. PMID:15123241 doi:10.1016/j.chembiol.2004.03.013

Contents


PDB ID 1rgr

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