DC Field | Value | Language |
---|---|---|
dc.contributor.author | Sadowsky, JD | ko |
dc.contributor.author | Fairlie, WD | ko |
dc.contributor.author | Hadley, EB | ko |
dc.contributor.author | Lee, Hee-Seung | ko |
dc.contributor.author | Umezawa, N | ko |
dc.contributor.author | Nikolovska-Coleska, Z | ko |
dc.contributor.author | Wang, SM | ko |
dc.contributor.author | Huang, DCS | ko |
dc.contributor.author | Tomita, Y | ko |
dc.contributor.author | Gellman, SH | ko |
dc.date.accessioned | 2013-03-06T23:33:45Z | - |
dc.date.available | 2013-03-06T23:33:45Z | - |
dc.date.created | 2012-02-06 | - |
dc.date.created | 2012-02-06 | - |
dc.date.issued | 2007-01 | - |
dc.identifier.citation | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.129, no.1, pp.139 - 154 | - |
dc.identifier.issn | 0002-7863 | - |
dc.identifier.uri | http://hdl.handle.net/10203/88827 | - |
dc.description.abstract | The development of molecules that bind to specific protein surface sites and inhibit protein-protein interactions is a fundamental challenge in molecular recognition. New strategies for approaching this challenge could have important long-term ramifications in biology and medicine. We are exploring the concept that unnatural oligomers with well-defined conformations ("foldamers") can mimic protein secondary structural elements and thereby block specific protein-protein interactions. Here, we describe the identification and analysis of helical peptide-based foldamers that bind to a specific cleft on the anti-apoptotic protein Bcl-x(L) by mimicking an alpha-helical BH3 domain. Initial studies, employing a fluorescence polarization (FP) competition assay, revealed that among several alpha/beta- and beta-peptide foldamer backbones only alpha/beta-peptides intended to adopt 14/15-helical secondary structure display significant binding to Bcl-x(L). The most tightly binding Bcl-x(L) ligands are chimeric oligomers in which an N-terminal alpha/beta-peptide segment is fused to a C-terminal alpha-peptide segment ((alpha/beta+alpha)-peptides)). Sequence-affinity relationships were probed via standard and nonstandard techniques (alanine scanning and hydrophile scanning, respectively), and the results allowed us to construct a computational model of the ligand/Bcl-x(L) complex. Analytical ultracentrifugation with a high-affinity (alpha/beta+alpha)-peptide established 1:1 ligand: Bcl-x(L) stoichiometry under FP assay conditions. Binding selectivity studies with the most potent (alpha/beta+alpha)-peptide, conducted via surface plasmon resonance measurements, revealed that this ligand binds tightly to Bcl-w as well as to Bcl-x(L), while binding to Bcl-2 is somewhat weaker. No binding could be detected with Mcl-1. We show that our most potent (alpha/beta+alpha)-peptide can induce cytochrome C release from mitochondria, an early step in apoptosis, in cell lysates, and that this activity is dependent upon inhibition of protein-protein interactions involving Bcl-x(L). | - |
dc.language | English | - |
dc.publisher | AMER CHEMICAL SOC | - |
dc.subject | FLUORESCENCE POLARIZATION ASSAYS | - |
dc.subject | HELICAL SECONDARY STRUCTURE | - |
dc.subject | SMALL-MOLECULE ANTAGONISTS | - |
dc.subject | SHORT ALPHA/BETA-PEPTIDES | - |
dc.subject | AFFINITY-BASED SELECTION | - |
dc.subject | SPLIT-POOL SYNTHESIS | - |
dc.subject | BETA-PEPTIDES | - |
dc.subject | BCL-2 FAMILY | - |
dc.subject | PROMISCUOUS INHIBITORS | - |
dc.subject | BINDING PEPTIDES | - |
dc.title | (alpha/beta+alpha)-Peptide antagonists of BH3 Domain/Bcl-x(L) recognition: Toward general strategies for foldamer-based inhibition of protein-protein interactions | - |
dc.type | Article | - |
dc.identifier.wosid | 000243195100035 | - |
dc.identifier.scopusid | 2-s2.0-33846042156 | - |
dc.type.rims | ART | - |
dc.citation.volume | 129 | - |
dc.citation.issue | 1 | - |
dc.citation.beginningpage | 139 | - |
dc.citation.endingpage | 154 | - |
dc.citation.publicationname | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | - |
dc.identifier.doi | 10.1021/ja0662523 | - |
dc.contributor.localauthor | Lee, Hee-Seung | - |
dc.contributor.nonIdAuthor | Sadowsky, JD | - |
dc.contributor.nonIdAuthor | Fairlie, WD | - |
dc.contributor.nonIdAuthor | Hadley, EB | - |
dc.contributor.nonIdAuthor | Umezawa, N | - |
dc.contributor.nonIdAuthor | Nikolovska-Coleska, Z | - |
dc.contributor.nonIdAuthor | Wang, SM | - |
dc.contributor.nonIdAuthor | Huang, DCS | - |
dc.contributor.nonIdAuthor | Tomita, Y | - |
dc.contributor.nonIdAuthor | Gellman, SH | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordPlus | FLUORESCENCE POLARIZATION ASSAYS | - |
dc.subject.keywordPlus | HELICAL SECONDARY STRUCTURE | - |
dc.subject.keywordPlus | SMALL-MOLECULE ANTAGONISTS | - |
dc.subject.keywordPlus | SHORT ALPHA/BETA-PEPTIDES | - |
dc.subject.keywordPlus | AFFINITY-BASED SELECTION | - |
dc.subject.keywordPlus | SPLIT-POOL SYNTHESIS | - |
dc.subject.keywordPlus | BETA-PEPTIDES | - |
dc.subject.keywordPlus | BCL-2 FAMILY | - |
dc.subject.keywordPlus | PROMISCUOUS INHIBITORS | - |
dc.subject.keywordPlus | BINDING PEPTIDES | - |
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