2010
DOI: 10.1002/anie.201005575
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Engineering Peptide Inhibitors To Overcome PDZ Binding Promiscuity

Abstract: Design of inhibitors: PDZ domains are conserved modules regulating the localization and activity of effector proteins. An integrated approach has been developed that uses peptide‐array screening technologies and fluorescence polarization measurements to analyze five promiscuous PDZ domains. By combining both methods, a highly specific inhibitor (iCAL3610=ANSRWPTSII) for one of the five PDZ domains was designed.

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Cited by 47 publications
(89 citation statements)
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“…The K i values were calculated using a SOLVERbased least squares fitting algorithm in EXCEL (9,21). Values for weakly interacting peptides, defined as K i Ͼ 1000 M, were calculated by comparison with modeled displacement isotherms (9).…”
Section: Methodsmentioning
confidence: 99%
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“…The K i values were calculated using a SOLVERbased least squares fitting algorithm in EXCEL (9,21). Values for weakly interacting peptides, defined as K i Ͼ 1000 M, were calculated by comparison with modeled displacement isotherms (9).…”
Section: Methodsmentioning
confidence: 99%
“…Multidomain PDZ proteins also form scaffolds that regulate the assembly and composition of supermolecular complexes (2). As a result, PDZ domains play key roles in a number of human diseases, including cancer (3)(4)(5), epilepsy and pain (6,7), and cystic fibrosis (8,9). * This work was supported, in whole or in part, by National Institutes of Health Although experimental studies have characterized target preferences for a large number of PDZ domains (10,11), binding information is absent or available only for a limited subset of ligands for many other domains.…”
mentioning
confidence: 99%
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“…Spot signal intensities can then be correlated to the measured binding affinities, yielding a semi-quantitative binding assay. This approach has been demonstrated with the yeast SH3 interactome [33] and for the CAL PDZ domain interaction [59]. Such follow-up studies are important if peptide arrays are used to develop effective inhibitors or assess the biological relevance of the observed binding events (specific versus unspecific).…”
Section: Qualitative Explorative Investigations and Quantitative Analmentioning
confidence: 99%
“…Such an inverted peptide array requires a special, ether-type cellulose membrane called N-CAPE membrane [76] with amino-loading capacities of 200-800 nmol/cm 2 . More recently, cystic fibrosis research focused on finding a selective CAL PDZ inhibitory peptide by applying an integrated synthetic peptide array approach designed for PDZ domain screening [59]. The screening discovered a peptide that selectively inhib- its the CAL PDZ domain, which in turn extends the half-life of the DF508-CFTR protein responsible for cystic fibrosis.…”
Section: Cellulose Membrane Modifications and Inverted Peptide Arraysmentioning
confidence: 99%