Biochemical Basis for Enhanced Binding of Peptide Dimers to X-Linked Inhibitor of Apoptosis Protein†
Identifieur interne : 001410 ( Main/Exploration ); précédent : 001409; suivant : 001411Biochemical Basis for Enhanced Binding of Peptide Dimers to X-Linked Inhibitor of Apoptosis Protein†
Auteurs : Kathryn E. Splan [États-Unis] ; John E. Allen [États-Unis] ; George L. Mclendon [États-Unis]Source :
- Biochemistry [ 0006-2960 ] ; 2007.
Abstract
XIAP (X-linked inhibitor of apoptosis protein) is involved in the mediation of programmed cell death and, therefore, is a target for the development of cancer therapeutics. Peptide mimetics based upon Smac, the natural binding partner of XIAP, and specifically, dimeric peptides, have shown great promise in drug development. In the present work, the basis for enhanced dimer efficacy has been explored. Comparisons are made between the peptide binding site on the BIR3 domain of XIAP alone (residues 238−358) and a less truncated construct that includes both BIR2 and BIR3 domains (residues 151−350). This contingency differentially enhances the binding of dimeric tetrapeptides, potentially by providing additional hydrophobic binding surface. The effect of BIR2 on the BIR3 binding site is sustained, even if the BIR2 binding site is disrupted by mutagenesis, as shown by both a fluorescent competition assay and a polarity sensitive dye, badan. FRET measurements reveal an observed separation of ≥45 Å between the BIR2 and BIR3 peptide binding pockets, thereby precluding a direct simultaneous interaction of the dimer molecules with both binding domains. Furthermore, variations in the linker length between dimeric tetrapeptides did not show a predictable trend in binding affinities, suggesting that local concentration effects were also an unlikely explanation for the enhanced dimeric affinities. Taken together, the results suggest that enhanced binding of dimeric peptides likely reflects the increased hydrophobic surface area on or near the BIR3 site and have significant ramifications for the design of therapeutics that target this class of proteins.
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DOI: 10.1021/bi061938t
Affiliations:
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of Apoptosis Protein<ref type="bib" target="#bi061938tAF2">†</ref></title><author><name sortKey="Splan, Kathryn E" sort="Splan, Kathryn E" uniqKey="Splan K" first="Kathryn E." last="Splan">Kathryn E. Splan</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Department of Chemistry, Macalester College, 1600 Grand Avenue, St. Paul, Minnesota 55105, and Department of Chemistry,Duke University, P.O. Box 90317, Durham</wicri:cityArea></affiliation><affiliation></affiliation><affiliation></affiliation></author><author><name sortKey="Allen, John E" sort="Allen, John E" uniqKey="Allen J" first="John E." last="Allen">John E. Allen</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Department of Chemistry, Macalester College, 1600 Grand Avenue, St. Paul, Minnesota 55105, and Department of Chemistry,Duke University, P.O. Box 90317, Durham</wicri:cityArea></affiliation><affiliation></affiliation></author><author><name sortKey="Mclendon, George L" sort="Mclendon, George L" uniqKey="Mclendon G" first="George L." last="Mclendon">George L. Mclendon</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName><wicri:cityArea>Department of Chemistry, Macalester College, 1600 Grand Avenue, St. Paul, Minnesota 55105, and Department of Chemistry,Duke University, P.O. Box 90317, Durham</wicri:cityArea></affiliation><affiliation></affiliation><affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Biochemistry</title><title level="j" type="abbrev">Biochemistry</title><idno type="ISSN">0006-2960</idno><idno type="eISSN">1520-4995</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published" when="2007-10-02">2007</date><date when="2007-10-23">2007</date><biblScope unit="vol">46</biblScope><biblScope unit="issue">42</biblScope><biblScope unit="page" from="11938">11938</biblScope><biblScope unit="page" to="11944">11944</biblScope></imprint><idno type="ISSN">0006-2960</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2960</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">XIAP (X-linked inhibitor of apoptosis protein) is involved in the mediation of programmed cell death and, therefore, is a target for the development of cancer therapeutics. Peptide mimetics based upon Smac, the natural binding partner of XIAP, and specifically, dimeric peptides, have shown great promise in drug development. In the present work, the basis for enhanced dimer efficacy has been explored. Comparisons are made between the peptide binding site on the BIR3 domain of XIAP alone (residues 238−358) and a less truncated construct that includes both BIR2 and BIR3 domains (residues 151−350). This contingency differentially enhances the binding of dimeric tetrapeptides, potentially by providing additional hydrophobic binding surface. The effect of BIR2 on the BIR3 binding site is sustained, even if the BIR2 binding site is disrupted by mutagenesis, as shown by both a fluorescent competition assay and a polarity sensitive dye, badan. FRET measurements reveal an observed separation of ≥45 Å between the BIR2 and BIR3 peptide binding pockets, thereby precluding a direct simultaneous interaction of the dimer molecules with both binding domains. Furthermore, variations in the linker length between dimeric tetrapeptides did not show a predictable trend in binding affinities, suggesting that local concentration effects were also an unlikely explanation for the enhanced dimeric affinities. Taken together, the results suggest that enhanced binding of dimeric peptides likely reflects the increased hydrophobic surface area on or near the BIR3 site and have significant ramifications for the design of therapeutics that target this class of proteins.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li></region></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Splan, Kathryn E" sort="Splan, Kathryn E" uniqKey="Splan K" first="Kathryn E." last="Splan">Kathryn E. Splan</name></region><name sortKey="Allen, John E" sort="Allen, John E" uniqKey="Allen J" first="John E." last="Allen">John E. Allen</name><name sortKey="Mclendon, George L" sort="Mclendon, George L" uniqKey="Mclendon G" first="George L." last="Mclendon">George L. Mclendon</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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