Source:http://linkedlifedata.com/resource/pubmed/id/17199293
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1
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pubmed:dateCreated |
2007-1-3
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pubmed:abstractText |
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-xL 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-xL. The most tightly binding Bcl-xL 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-xL complex. Analytical ultracentrifugation with a high-affinity (alpha/beta + alpha)-peptide established 1:1 ligand:Bcl-xL 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-xL, 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-xL.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Alanine,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochromes c,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-X Protein
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0002-7863
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pubmed:author |
pubmed-author:FairlieW DouglasWD,
pubmed-author:GellmanSamuel HSH,
pubmed-author:HadleyErik BEB,
pubmed-author:HuangDavid C SDC,
pubmed-author:LeeHee-SeungHS,
pubmed-author:Nikolovska-ColeskaZanetaZ,
pubmed-author:SadowskyJack DJD,
pubmed-author:TomitaYorkY,
pubmed-author:UmezawaNaokiN,
pubmed-author:WangShaomengS
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pubmed:issnType |
Print
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pubmed:day |
10
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pubmed:volume |
129
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
139-54
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pubmed:dateRevised |
2007-12-3
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pubmed:meshHeading |
pubmed-meshheading:17199293-Alanine,
pubmed-meshheading:17199293-Amino Acid Sequence,
pubmed-meshheading:17199293-Apoptosis,
pubmed-meshheading:17199293-Cytochromes c,
pubmed-meshheading:17199293-Drug Design,
pubmed-meshheading:17199293-Humans,
pubmed-meshheading:17199293-Ligands,
pubmed-meshheading:17199293-Mitochondria,
pubmed-meshheading:17199293-Molecular Sequence Data,
pubmed-meshheading:17199293-Peptides,
pubmed-meshheading:17199293-Protein Structure, Secondary,
pubmed-meshheading:17199293-Protein Structure, Tertiary,
pubmed-meshheading:17199293-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:17199293-Recombinant Fusion Proteins,
pubmed-meshheading:17199293-Structure-Activity Relationship,
pubmed-meshheading:17199293-bcl-X Protein
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pubmed:year |
2007
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pubmed:articleTitle |
(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions.
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pubmed:affiliation |
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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