Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action
Glucagon and glucagon‐like peptide‐1 (GLP‐1)are two structurally related hormones that acutely regulate glucose control in opposite directions through homologous receptors. The molecular basis for selectivity between these two hormones and their receptors is of physiological and medicinal importance...
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Veröffentlicht in: | Journal of peptide science 2011-03, Vol.17 (3), p.218-225 |
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description | Glucagon and glucagon‐like peptide‐1 (GLP‐1)are two structurally related hormones that acutely regulate glucose control in opposite directions through homologous receptors. The molecular basis for selectivity between these two hormones and their receptors is of physiological and medicinal importance. The application of co‐agonists to enhance body weight reduction and correct multiple abnormalities associated with the metabolic syndrome has recently been reported. Substitution of amino acids 16, 18, and 20 in glucagon with those found in GLP‐1 and exendin‐4 were identified as partial contributors to balanced, high potency receptor action. The amidation of the C‐terminus was an additional glucagon‐based structural change observed to be of seminal importance to discriminate recognition by both receptors. In this work, the molecular basis for receptor selectivity associated with differences in C‐terminal peptide sequence has been determined. A single charge inversion in glucagon and GLP‐1 receptor sequence at position 68* was determined to significantly alter hormone action. Changing E68* in GLP‐1R to the corresponding Lys of GCGR reduced receptor activity for natural GLP‐1 hormones by eightfold. The enhanced C‐terminal positive charges in GLP‐1 peptides favor the native receptor's negative charge at position 68*, while the unfavorable interaction with the C‐terminal acid of native glucagon is minimized by amidation. The extension of these observations to other glucagon‐related hormones such as oxyntomodulin and exendin, as well as other related receptors such as GIPR, should assist in the assembly of additional hormones with broadened pharmacology. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.
The activity of a structurally diverse set of glucagon‐like peptides was assessed at the GLP‐1 receptor and two related single site mutants. This study reveals that single amino acid differences at positions 68 & 128 in GLP‐1R influence selectivity for ligand action. |
doi_str_mv | 10.1002/psc.1317 |
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The activity of a structurally diverse set of glucagon‐like peptides was assessed at the GLP‐1 receptor and two related single site mutants. This study reveals that single amino acid differences at positions 68 & 128 in GLP‐1R influence selectivity for ligand action.</description><identifier>ISSN: 1075-2617</identifier><identifier>ISSN: 1099-1387</identifier><identifier>EISSN: 1099-1387</identifier><identifier>DOI: 10.1002/psc.1317</identifier><identifier>PMID: 21308878</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Amino Acid Sequence ; Amino acid substitution ; Body weight ; C-Terminus ; Cell Line ; GLP-1 ; Glucagon ; Glucagon - chemistry ; Glucagon - genetics ; Glucagon - metabolism ; Glucagon-like peptide 1 ; Glucagon-Like Peptide 1 - chemistry ; Glucagon-Like Peptide 1 - genetics ; Glucagon-Like Peptide 1 - metabolism ; Glucagon-Like Peptide-1 Receptor ; glucagons ; Glucose ; GPCR ; Hormones ; Humans ; Inversion ; Metabolic disorders ; Molecular Sequence Data ; Mutation ; Pharmacology ; Protein Binding ; receptor mutagenesis ; Receptors, Glucagon - chemistry ; Receptors, Glucagon - genetics ; Receptors, Glucagon - metabolism</subject><ispartof>Journal of peptide science, 2011-03, Vol.17 (3), p.218-225</ispartof><rights>Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3917-ec533d54fe60bebc5e9e04c4c6b536709a472da528618e58162d6b21139d333c3</citedby><cites>FETCH-LOGICAL-c3917-ec533d54fe60bebc5e9e04c4c6b536709a472da528618e58162d6b21139d333c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpsc.1317$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpsc.1317$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21308878$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Day, Jonathan W.</creatorcontrib><creatorcontrib>Li, Pengyun</creatorcontrib><creatorcontrib>Patterson, James T.</creatorcontrib><creatorcontrib>Chabenne, Joe</creatorcontrib><creatorcontrib>Chabenne, Maria DiMarchi</creatorcontrib><creatorcontrib>Gelfanov, Vasily M.</creatorcontrib><creatorcontrib>DiMarchi, Richard D.</creatorcontrib><title>Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action</title><title>Journal of peptide science</title><addtitle>J. Peptide Sci</addtitle><description>Glucagon and glucagon‐like peptide‐1 (GLP‐1)are two structurally related hormones that acutely regulate glucose control in opposite directions through homologous receptors. The molecular basis for selectivity between these two hormones and their receptors is of physiological and medicinal importance. The application of co‐agonists to enhance body weight reduction and correct multiple abnormalities associated with the metabolic syndrome has recently been reported. Substitution of amino acids 16, 18, and 20 in glucagon with those found in GLP‐1 and exendin‐4 were identified as partial contributors to balanced, high potency receptor action. The amidation of the C‐terminus was an additional glucagon‐based structural change observed to be of seminal importance to discriminate recognition by both receptors. In this work, the molecular basis for receptor selectivity associated with differences in C‐terminal peptide sequence has been determined. A single charge inversion in glucagon and GLP‐1 receptor sequence at position 68* was determined to significantly alter hormone action. Changing E68* in GLP‐1R to the corresponding Lys of GCGR reduced receptor activity for natural GLP‐1 hormones by eightfold. The enhanced C‐terminal positive charges in GLP‐1 peptides favor the native receptor's negative charge at position 68*, while the unfavorable interaction with the C‐terminal acid of native glucagon is minimized by amidation. The extension of these observations to other glucagon‐related hormones such as oxyntomodulin and exendin, as well as other related receptors such as GIPR, should assist in the assembly of additional hormones with broadened pharmacology. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.
The activity of a structurally diverse set of glucagon‐like peptides was assessed at the GLP‐1 receptor and two related single site mutants. This study reveals that single amino acid differences at positions 68 & 128 in GLP‐1R influence selectivity for ligand action.</description><subject>Amino Acid Sequence</subject><subject>Amino acid substitution</subject><subject>Body weight</subject><subject>C-Terminus</subject><subject>Cell Line</subject><subject>GLP-1</subject><subject>Glucagon</subject><subject>Glucagon - chemistry</subject><subject>Glucagon - genetics</subject><subject>Glucagon - metabolism</subject><subject>Glucagon-like peptide 1</subject><subject>Glucagon-Like Peptide 1 - chemistry</subject><subject>Glucagon-Like Peptide 1 - genetics</subject><subject>Glucagon-Like Peptide 1 - metabolism</subject><subject>Glucagon-Like Peptide-1 Receptor</subject><subject>glucagons</subject><subject>Glucose</subject><subject>GPCR</subject><subject>Hormones</subject><subject>Humans</subject><subject>Inversion</subject><subject>Metabolic disorders</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Pharmacology</subject><subject>Protein Binding</subject><subject>receptor mutagenesis</subject><subject>Receptors, Glucagon - chemistry</subject><subject>Receptors, Glucagon - genetics</subject><subject>Receptors, Glucagon - metabolism</subject><issn>1075-2617</issn><issn>1099-1387</issn><issn>1099-1387</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0Eou2CxC9AvsElxY7jryPaQvkoCxIgjpbjzO6aZuNgOy0r8eNx1GU5wWne0Tx65vAi9ISSc0pI_WJM7pwyKu-hU0q0rihT8v6cJa9qQeUJOkvpOyHlxsVDdFJTRpSS6hT9Wm5t3AD2ww3E5MOAbcZjSD7PWSgc1jhvAW_6ydnNfB6641L1_hrwCGP2HVQUR3Alh5hwmsYxxFwC9OCyv_F5X37gbYi7MAC2bvY_Qg_Wtk_w-DAX6OvrV1-Wb6qrj5dvly-vKsc0lRU4zljHmzUI0kLrOGggjWucaDkTkmjbyLqzvFaCKuCKiroTbU0p0x1jzLEFenbnHWP4MUHKZueTg763A4QpGcVpIwUvXxbo-X9JSqjUspZa_0VdDClFWJsx-p2N-wKZuRVTWjFzKwV9erBO7Q66I_inhgJUd8Ct72H_T5H59Hl5EB54nzL8PPI2XhshmeTm2-rSrN7LD6sVe2cu2G92lqX9</recordid><startdate>201103</startdate><enddate>201103</enddate><creator>Day, Jonathan W.</creator><creator>Li, Pengyun</creator><creator>Patterson, James T.</creator><creator>Chabenne, Joe</creator><creator>Chabenne, Maria DiMarchi</creator><creator>Gelfanov, Vasily M.</creator><creator>DiMarchi, Richard D.</creator><general>John Wiley & Sons, Ltd</general><scope>BSCLL</scope><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>201103</creationdate><title>Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action</title><author>Day, Jonathan W. ; Li, Pengyun ; Patterson, James T. ; Chabenne, Joe ; Chabenne, Maria DiMarchi ; Gelfanov, Vasily M. ; DiMarchi, Richard D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3917-ec533d54fe60bebc5e9e04c4c6b536709a472da528618e58162d6b21139d333c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Amino Acid Sequence</topic><topic>Amino acid substitution</topic><topic>Body weight</topic><topic>C-Terminus</topic><topic>Cell Line</topic><topic>GLP-1</topic><topic>Glucagon</topic><topic>Glucagon - chemistry</topic><topic>Glucagon - genetics</topic><topic>Glucagon - metabolism</topic><topic>Glucagon-like peptide 1</topic><topic>Glucagon-Like Peptide 1 - chemistry</topic><topic>Glucagon-Like Peptide 1 - genetics</topic><topic>Glucagon-Like Peptide 1 - metabolism</topic><topic>Glucagon-Like Peptide-1 Receptor</topic><topic>glucagons</topic><topic>Glucose</topic><topic>GPCR</topic><topic>Hormones</topic><topic>Humans</topic><topic>Inversion</topic><topic>Metabolic disorders</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Pharmacology</topic><topic>Protein Binding</topic><topic>receptor mutagenesis</topic><topic>Receptors, Glucagon - chemistry</topic><topic>Receptors, Glucagon - genetics</topic><topic>Receptors, Glucagon - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Day, Jonathan W.</creatorcontrib><creatorcontrib>Li, Pengyun</creatorcontrib><creatorcontrib>Patterson, James T.</creatorcontrib><creatorcontrib>Chabenne, Joe</creatorcontrib><creatorcontrib>Chabenne, Maria DiMarchi</creatorcontrib><creatorcontrib>Gelfanov, Vasily M.</creatorcontrib><creatorcontrib>DiMarchi, Richard D.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of peptide science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Day, Jonathan W.</au><au>Li, Pengyun</au><au>Patterson, James T.</au><au>Chabenne, Joe</au><au>Chabenne, Maria DiMarchi</au><au>Gelfanov, Vasily M.</au><au>DiMarchi, Richard D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action</atitle><jtitle>Journal of peptide science</jtitle><addtitle>J. Peptide Sci</addtitle><date>2011-03</date><risdate>2011</risdate><volume>17</volume><issue>3</issue><spage>218</spage><epage>225</epage><pages>218-225</pages><issn>1075-2617</issn><issn>1099-1387</issn><eissn>1099-1387</eissn><abstract>Glucagon and glucagon‐like peptide‐1 (GLP‐1)are two structurally related hormones that acutely regulate glucose control in opposite directions through homologous receptors. The molecular basis for selectivity between these two hormones and their receptors is of physiological and medicinal importance. The application of co‐agonists to enhance body weight reduction and correct multiple abnormalities associated with the metabolic syndrome has recently been reported. Substitution of amino acids 16, 18, and 20 in glucagon with those found in GLP‐1 and exendin‐4 were identified as partial contributors to balanced, high potency receptor action. The amidation of the C‐terminus was an additional glucagon‐based structural change observed to be of seminal importance to discriminate recognition by both receptors. In this work, the molecular basis for receptor selectivity associated with differences in C‐terminal peptide sequence has been determined. A single charge inversion in glucagon and GLP‐1 receptor sequence at position 68* was determined to significantly alter hormone action. Changing E68* in GLP‐1R to the corresponding Lys of GCGR reduced receptor activity for natural GLP‐1 hormones by eightfold. The enhanced C‐terminal positive charges in GLP‐1 peptides favor the native receptor's negative charge at position 68*, while the unfavorable interaction with the C‐terminal acid of native glucagon is minimized by amidation. The extension of these observations to other glucagon‐related hormones such as oxyntomodulin and exendin, as well as other related receptors such as GIPR, should assist in the assembly of additional hormones with broadened pharmacology. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.
The activity of a structurally diverse set of glucagon‐like peptides was assessed at the GLP‐1 receptor and two related single site mutants. This study reveals that single amino acid differences at positions 68 & 128 in GLP‐1R influence selectivity for ligand action.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>21308878</pmid><doi>10.1002/psc.1317</doi><tpages>8</tpages></addata></record> |
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subjects | Amino Acid Sequence Amino acid substitution Body weight C-Terminus Cell Line GLP-1 Glucagon Glucagon - chemistry Glucagon - genetics Glucagon - metabolism Glucagon-like peptide 1 Glucagon-Like Peptide 1 - chemistry Glucagon-Like Peptide 1 - genetics Glucagon-Like Peptide 1 - metabolism Glucagon-Like Peptide-1 Receptor glucagons Glucose GPCR Hormones Humans Inversion Metabolic disorders Molecular Sequence Data Mutation Pharmacology Protein Binding receptor mutagenesis Receptors, Glucagon - chemistry Receptors, Glucagon - genetics Receptors, Glucagon - metabolism |
title | Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action |
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