Bivalent peptides as PDZ domain ligands

Klosi, Edvin; Saro, Dorina; Spaller, Mark R.

doi:10.1016/j.bmcl.2007.09.035

Cited by 8 publications

(4 citation statements)

References 32 publications

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“…We had several options, based on our prior experience in devising ligand design strategies for the PDZ domain. These involved designs based not only on linear peptides composed of standard or nonproteinogenic residues but also cyclic, , multivalent, and chemically modified peptides . After reviewing all of these approaches, we elected to use the binding sequence represented by CR1023 and to implement the organic acid modification strategy that had successfully generated high-affinity inhibitors for the PDZ3 domain of PSD-95 …”

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confidence: 99%

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

et al. 2012

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GIPC (GAIP-interacting protein, C terminus) represents a new target class for the discovery of chemotherapeutics. While many of the current generation of anticancer agents function by directly binding to intracellular kinases or cell surface receptors, the disruption of cytosolic protein-protein interactions mediated by non-enzymatic domains is an underdeveloped avenue for inhibiting cancer growth. One such example is the PDZ domain of GIPC. Previously we developed a molecular probe, the cell permeable octapeptide CR1023 (N-myristoyl-PSQSSSEA), which diminished proliferation of pancreatic cancer cells. We have expanded upon that discovery using a chemical modification approach, and here report a series of cell permeable, side chain-modified lipopeptides that target the GIPC PDZ domain in vitro and in vivo. These peptides exhibit significant activity against pancreatic and breast cancers, both in vitro and in animal models. CR1166 (N-myristoyl-PSQSK(εN-4-bromobenzoyl)SK(εN-4-bromobenzoyl)A), bearing two halogenated aromatic units on alternate side chains, was found to be the most active compound, with pronounced down-regulation of EGFR/1GF-1R expression. We hypothesize that these organic acid-modified residues extend the productive reach of the peptide beyond the canonical binding pocket, which defines the limit of accessibility for the native proteinogenic sequences that the PDZ domain has evolved to recognize. Cell permeability is achieved with N-terminal lipidation using myristate, rather than a larger CPP (cell-penetrating peptide) sequence. This, in conjunction with optimization of targeting through side chain modification, has yielded an approach that will allow the discovery and development of next-generation cellular probes for GIPC PDZ as well as other PDZ domains.

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confidence: 99%

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

et al. 2012

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“…The concept of enhancing the gephyrin-binding affinity of its cognate receptors by dimerization presented in this study opens new avenues of research: (1) Variants of the dimeric peptide may be used for future crystallographic studies of low affinity GABA A R subunits, − which so far have not been amenable to crystallization in our hands. (2) By competing with naturally occurring receptor–gephyrin interactions, the dimerized β19 fragment and related compounds might be used as tools to specifically target gephyrin’s receptor binding activity in a fashion analogous to compounds targeting interactions between PDZ domains and excitatory neurotransmitter receptors or other disease relevant ligands. − …”

Section: Resultsmentioning

confidence: 99%

Modulation of Gephyrin-Glycine Receptor Affinity by Multivalency

2014

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Gephyrin is a major determinant for the accumulation and anchoring of glycine receptors (GlyRs) and the majority of γ-aminobutyric acid type A receptors (GABAARs) at postsynaptic sites. Here we explored the interaction of gephyrin with a dimeric form of a GlyR β-subunit receptor-derived peptide. A 2 Å crystal structure of the C-terminal domain of gephyrin (GephE) in complex with a 15-residue peptide derived from the GlyR β-subunit defined the core binding site, which we targeted with the dimeric peptide. Biophysical analyses via differential scanning calorimetry (DSC), thermofluor, and isothermal titration calorimetry (ITC) demonstrated that this dimeric ligand is capable of binding simultaneously to two receptor binding sites and that this multivalency results in a 25-fold enhanced affinity. Our study therefore suggests that the oligomeric state of gephyrin and the number of gephyrin-binding subunits in the pentameric GABAARs and GlyRs together control postsynaptic receptor clustering.

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“…1,2 Hence, PDZ domains are also referred as peptide recognition modules similar to SH3, PTB, WW, etc. Since, PDZ domains are involved in a variety of biologically important functions, 3 disruption of these interactions leads to several human diseases like congenital sensorineural deafness, vestibular dysfunction, blindness and Dejerine−Sottas neuropathy, etc. 4−6 In view of the functional importance of PDZ domains, a number of studies have attempted to decipher the substrate specificities of PDZ domains.…”

Section: ■ Introductionmentioning

confidence: 99%

“…PDZ domains are 100 amino acids long modular protein domains, which mediate protein–protein interactions by recognizing short peptide stretches on C-terminus of their interaction partners. , Hence, PDZ domains are also referred as peptide recognition modules similar to SH3, PTB, WW, etc. Since, PDZ domains are involved in a variety of biologically important functions, disruption of these interactions leads to several human diseases like congenital sensorineural deafness, vestibular dysfunction, blindness and Dejerine–Sottas neuropathy, etc. − In view of the functional importance of PDZ domains, a number of studies have attempted to decipher the substrate specificities of PDZ domains. , PDZ domains have been divided into three classes, namely class I, class II and class III, − based on the sequence motifs present in the C-terminal peptide stretches of their interaction partners. Class I PDZ domains prefer peptides containing X-S/T-X-φ-COOH, class II recognizes X-φ-X-φ-COOH, while class III recognizes X-D/E-X-φ-COOH motifs. , The crystal structures of PDZ domains in complex with substrate peptides have provided a structural basis for the recognition of above-mentioned sequence motifs by PDZ domains.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Multiscale Approach for Identification of Interaction Partners of PDZ Domains

Tiwari

Mohanty

2014

J. Chem. Inf. Model.

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PDZ domains are peptide recognition modules which mediate specific protein-protein interactions and are known to have a complex specificity landscape. We have developed a novel structure-based multiscale approach which identifies crucial specificity determining residues (SDRs) of PDZ domains from explicit solvent molecular dynamics (MD) simulations on PDZ-peptide complexes and uses these SDRs in combination with knowledge-based scoring functions for proteomewide identification of their interaction partners. Multiple explicit solvent simulations ranging from 5 to 50 ns duration have been carried out on 28 PDZ-peptide complexes with known binding affinities. MM/PBSA binding energy values calculated from these simulations show a correlation coefficient of 0.755 with the experimental binding affinities. On the basis of the SDRs of PDZ domains identified by MD simulations, we have developed a simple scoring scheme for evaluating binding energies for PDZ-peptide complexes using residue based statistical pair potentials. This multiscale approach has been benchmarked on a mouse PDZ proteome array data set by calculating the binding energies for 217 different substrate peptides in binding pockets of 64 different mouse PDZ domains. Receiver operating characteristic (ROC) curve analysis indicates that, the area under curve (AUC) values for binder vs nonbinder classification by our structure based method is 0.780. Our structure based method does not require experimental PDZ-peptide binding data for training.

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Bivalent peptides as PDZ domain ligands

Cited by 8 publications

References 32 publications

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

Modulation of Gephyrin-Glycine Receptor Affinity by Multivalency

Structure-Based Multiscale Approach for Identification of Interaction Partners of PDZ Domains

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