Structure-Based Design of Short Peptide Ligands Binding onto the E. coli Processivity Ring
The multimeric DNA sliding clamps confer high processivity to replicative DNA polymerases and are also binding platforms for various enzymes involved in DNA metabolism. These enzymes interact with the clamp through a small peptide that binds into a hydrophobic pocket which is a potential target for...
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Veröffentlicht in: | Journal of medicinal chemistry 2011-07, Vol.54 (13), p.4627-4637 |
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container_title | Journal of medicinal chemistry |
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creator | Wolff, Philippe Oliéric, Vincent Briand, Jean Paul Chaloin, Olivier Dejaegere, Annick Dumas, Philippe Ennifar, Eric Guichard, Gilles Wagner, Jérôme Burnouf, Dominique Y |
description | The multimeric DNA sliding clamps confer high processivity to replicative DNA polymerases and are also binding platforms for various enzymes involved in DNA metabolism. These enzymes interact with the clamp through a small peptide that binds into a hydrophobic pocket which is a potential target for the development of new antibacterial compounds. Starting from a generic heptapeptide, we used a structure-based strategy to improve the design of new peptide ligands. Chemical modifications at specific residues result in a dramatic increase of the interaction as measured by SPR and ITC. The affinity of our best hits was improved by 2 orders of magnitude as compared to the natural ligand, reaching 10–8 M range. The molecular basis of the interactions was analyzed by solving the co-crystal structures of the most relevant peptides bound to the clamp and reveals how chemical modifications establish new contacts and contributes to an increased affinity of the ligand. |
doi_str_mv | 10.1021/jm200311m |
format | Article |
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These enzymes interact with the clamp through a small peptide that binds into a hydrophobic pocket which is a potential target for the development of new antibacterial compounds. Starting from a generic heptapeptide, we used a structure-based strategy to improve the design of new peptide ligands. Chemical modifications at specific residues result in a dramatic increase of the interaction as measured by SPR and ITC. The affinity of our best hits was improved by 2 orders of magnitude as compared to the natural ligand, reaching 10–8 M range. 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Med. Chem</addtitle><description>The multimeric DNA sliding clamps confer high processivity to replicative DNA polymerases and are also binding platforms for various enzymes involved in DNA metabolism. These enzymes interact with the clamp through a small peptide that binds into a hydrophobic pocket which is a potential target for the development of new antibacterial compounds. Starting from a generic heptapeptide, we used a structure-based strategy to improve the design of new peptide ligands. Chemical modifications at specific residues result in a dramatic increase of the interaction as measured by SPR and ITC. The affinity of our best hits was improved by 2 orders of magnitude as compared to the natural ligand, reaching 10–8 M range. The molecular basis of the interactions was analyzed by solving the co-crystal structures of the most relevant peptides bound to the clamp and reveals how chemical modifications establish new contacts and contributes to an increased affinity of the ligand.</description><subject>Biochemistry, Molecular Biology</subject><subject>Crystallography, X-Ray</subject><subject>DNA Polymerase beta</subject><subject>DNA Polymerase beta - chemistry</subject><subject>DNA Polymerase III</subject><subject>DNA Polymerase III - chemistry</subject><subject>Drug Design</subject><subject>Escherichia coli</subject><subject>Escherichia coli - chemistry</subject><subject>Escherichia coli Proteins</subject><subject>Escherichia coli Proteins - chemistry</subject><subject>Life Sciences</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular biology</subject><subject>Oligopeptides</subject><subject>Oligopeptides - chemical synthesis</subject><subject>Oligopeptides - chemistry</subject><subject>Protein Binding</subject><subject>Structure-Activity Relationship</subject><subject>Thermodynamics</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMFP2zAUh61p09oxDvsHJl-miUPg2Ulc59h2bEyqBBpw4WI59kvrKomL7SDx35OqrFx4l5_09Ok7fIR8Y3DOgLOLbccBcsa6D2TKSg5ZIaH4SKYAnGdc8HxCvsS4hT3E889kwplgFczElDzcpjCYNATMFjqipb8wunVPfUNvNz4keoO75CzSlVvr3ka6cL11_Zr6PnmaNkgvz6nxraM3wRuM0T259Ez_jchX8qnRbcTT1z0h978v75ZX2er6z9_lfJXpvJApw1wbtNKI_VmwpqxLQDGTjeRFzaqcFYVmwMSM5TVCxaCuZKFr0WDJjbT5CTk7eDe6VbvgOh2elddOXc1Xav8DEFBU1eyJjezPA7sL_nHAmFTnosG21T36ISopSxgDSvFmNcHHGLA5qhmofXV1rD6y31-tQ92hPZL_M4_AjwOgTVRbP4R-DPKO6AV2U4aj</recordid><startdate>20110714</startdate><enddate>20110714</enddate><creator>Wolff, Philippe</creator><creator>Oliéric, Vincent</creator><creator>Briand, Jean Paul</creator><creator>Chaloin, Olivier</creator><creator>Dejaegere, Annick</creator><creator>Dumas, Philippe</creator><creator>Ennifar, Eric</creator><creator>Guichard, Gilles</creator><creator>Wagner, Jérôme</creator><creator>Burnouf, Dominique Y</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-3569-7771</orcidid><orcidid>https://orcid.org/0000-0002-2584-7502</orcidid><orcidid>https://orcid.org/0000-0002-5076-846X</orcidid><orcidid>https://orcid.org/0000-0003-3045-4452</orcidid><orcidid>https://orcid.org/0000-0002-7478-1925</orcidid></search><sort><creationdate>20110714</creationdate><title>Structure-Based Design of Short Peptide Ligands Binding onto the E. coli Processivity Ring</title><author>Wolff, Philippe ; Oliéric, Vincent ; Briand, Jean Paul ; Chaloin, Olivier ; Dejaegere, Annick ; Dumas, Philippe ; Ennifar, Eric ; Guichard, Gilles ; Wagner, Jérôme ; Burnouf, Dominique Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-e3aced8c66666d0dc5b50e678f824b193144a1016713be0910b984ab6fe52c8d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Biochemistry, Molecular Biology</topic><topic>Crystallography, X-Ray</topic><topic>DNA Polymerase beta</topic><topic>DNA Polymerase beta - chemistry</topic><topic>DNA Polymerase III</topic><topic>DNA Polymerase III - chemistry</topic><topic>Drug Design</topic><topic>Escherichia coli</topic><topic>Escherichia coli - chemistry</topic><topic>Escherichia coli Proteins</topic><topic>Escherichia coli Proteins - chemistry</topic><topic>Life Sciences</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular biology</topic><topic>Oligopeptides</topic><topic>Oligopeptides - chemical synthesis</topic><topic>Oligopeptides - chemistry</topic><topic>Protein Binding</topic><topic>Structure-Activity Relationship</topic><topic>Thermodynamics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wolff, Philippe</creatorcontrib><creatorcontrib>Oliéric, Vincent</creatorcontrib><creatorcontrib>Briand, Jean Paul</creatorcontrib><creatorcontrib>Chaloin, Olivier</creatorcontrib><creatorcontrib>Dejaegere, Annick</creatorcontrib><creatorcontrib>Dumas, Philippe</creatorcontrib><creatorcontrib>Ennifar, Eric</creatorcontrib><creatorcontrib>Guichard, Gilles</creatorcontrib><creatorcontrib>Wagner, Jérôme</creatorcontrib><creatorcontrib>Burnouf, Dominique Y</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wolff, Philippe</au><au>Oliéric, Vincent</au><au>Briand, Jean Paul</au><au>Chaloin, Olivier</au><au>Dejaegere, Annick</au><au>Dumas, Philippe</au><au>Ennifar, Eric</au><au>Guichard, Gilles</au><au>Wagner, Jérôme</au><au>Burnouf, Dominique Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Based Design of Short Peptide Ligands Binding onto the E. coli Processivity Ring</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2011-07-14</date><risdate>2011</risdate><volume>54</volume><issue>13</issue><spage>4627</spage><epage>4637</epage><pages>4627-4637</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The multimeric DNA sliding clamps confer high processivity to replicative DNA polymerases and are also binding platforms for various enzymes involved in DNA metabolism. These enzymes interact with the clamp through a small peptide that binds into a hydrophobic pocket which is a potential target for the development of new antibacterial compounds. Starting from a generic heptapeptide, we used a structure-based strategy to improve the design of new peptide ligands. Chemical modifications at specific residues result in a dramatic increase of the interaction as measured by SPR and ITC. The affinity of our best hits was improved by 2 orders of magnitude as compared to the natural ligand, reaching 10–8 M range. 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subjects | Biochemistry, Molecular Biology Crystallography, X-Ray DNA Polymerase beta DNA Polymerase beta - chemistry DNA Polymerase III DNA Polymerase III - chemistry Drug Design Escherichia coli Escherichia coli - chemistry Escherichia coli Proteins Escherichia coli Proteins - chemistry Life Sciences Ligands Models, Molecular Molecular biology Oligopeptides Oligopeptides - chemical synthesis Oligopeptides - chemistry Protein Binding Structure-Activity Relationship Thermodynamics |
title | Structure-Based Design of Short Peptide Ligands Binding onto the E. coli Processivity Ring |
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