Production of a human neutralizing monoclonal antibody and its crystal structure in complex with ectodomain 3 of the interleukin-13 receptor α1
Gene deletion studies in mice have revealed critical roles for IL (interleukin)-4 and -13 in asthma development, with the latter controlling lung airways resistance and mucus secretion. We have now developed human neutralizing monoclonal antibodies against human IL-13Rα1 (IL-13 receptor α1) subunit...
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| Veröffentlicht in: | Biochemical journal 2013-04, Vol.451 (2), p.165-175 |
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| creator | Redpath, Nicholas T Xu, Yibin Wilson, Nicholas J Fabri, Louis J Baca, Manuel Andrews, Arna E Braley, Hal Lu, Ping Ireland, Cheryl Ernst, Robin E Woods, Andrea Forrest, Gail An, Zhiqiang Zaller, Dennis M Strohl, William R Luo, Cindy S Czabotar, Peter E Garrett, Thomas P J Hilton, Douglas J Nash, Andrew D Zhang, Jian-Guo Nicola, Nicos A |
| description | Gene deletion studies in mice have revealed critical roles for IL (interleukin)-4 and -13 in asthma development, with the latter controlling lung airways resistance and mucus secretion. We have now developed human neutralizing monoclonal antibodies against human IL-13Rα1 (IL-13 receptor α1) subunit that prevent activation of the receptor complex by both IL-4 and IL-13. We describe the crystal structures of the Fab fragment of antibody 10G5H6 alone and in complex with D3 (ectodomain 3) of IL-13Rα1. Although the structure showed significant domain swapping within a D3 dimer, we showed that Arg(230), Phe(233), Tyr(250), Gln(252) and Leu(293) in each D3 monomer and Ser(32), Asn(102) and Trp(103) in 10G5H6 Fab are the key interacting residues at the interface of the 10G5H6 Fab-D3 complex. One of the most striking contacts is the insertion of the ligand-contacting residue Leu(293) of D3 into a deep pocket on the surface of 10G5H6 Fab, and this appears to be a central determinant of the high binding affinity and neutralizing activity of the antibody. |
| doi_str_mv | 10.1042/BJ20121819 |
| format | Article |
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We have now developed human neutralizing monoclonal antibodies against human IL-13Rα1 (IL-13 receptor α1) subunit that prevent activation of the receptor complex by both IL-4 and IL-13. We describe the crystal structures of the Fab fragment of antibody 10G5H6 alone and in complex with D3 (ectodomain 3) of IL-13Rα1. Although the structure showed significant domain swapping within a D3 dimer, we showed that Arg(230), Phe(233), Tyr(250), Gln(252) and Leu(293) in each D3 monomer and Ser(32), Asn(102) and Trp(103) in 10G5H6 Fab are the key interacting residues at the interface of the 10G5H6 Fab-D3 complex. 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Xu, Yibin ; Wilson, Nicholas J ; Fabri, Louis J ; Baca, Manuel ; Andrews, Arna E ; Braley, Hal ; Lu, Ping ; Ireland, Cheryl ; Ernst, Robin E ; Woods, Andrea ; Forrest, Gail ; An, Zhiqiang ; Zaller, Dennis M ; Strohl, William R ; Luo, Cindy S ; Czabotar, Peter E ; Garrett, Thomas P J ; Hilton, Douglas J ; Nash, Andrew D ; Zhang, Jian-Guo ; Nicola, Nicos A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c287t-1f18c7da7fa0ef79e6f7f57f61af3c26c3bacc8e8027007bb0ce506820dbfad33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - chemistry</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - metabolism</topic><topic>Antibodies, Neutralizing - chemistry</topic><topic>Antibodies, Neutralizing - immunology</topic><topic>Antibodies, Neutralizing - metabolism</topic><topic>Binding Sites - immunology</topic><topic>Crystallography, X-Ray</topic><topic>Dimerization</topic><topic>Epitopes</topic><topic>Humans</topic><topic>Immunoglobulin Fab Fragments - chemistry</topic><topic>Interleukin-13 - immunology</topic><topic>Interleukin-13 - metabolism</topic><topic>Interleukin-13 Receptor alpha1 Subunit - chemistry</topic><topic>Interleukin-13 Receptor alpha1 Subunit - metabolism</topic><topic>Interleukin-4 - immunology</topic><topic>Interleukin-4 - metabolism</topic><topic>Leucine - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Protein Structure, Tertiary</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Redpath, Nicholas T</creatorcontrib><creatorcontrib>Xu, Yibin</creatorcontrib><creatorcontrib>Wilson, Nicholas J</creatorcontrib><creatorcontrib>Fabri, Louis J</creatorcontrib><creatorcontrib>Baca, Manuel</creatorcontrib><creatorcontrib>Andrews, Arna E</creatorcontrib><creatorcontrib>Braley, Hal</creatorcontrib><creatorcontrib>Lu, Ping</creatorcontrib><creatorcontrib>Ireland, Cheryl</creatorcontrib><creatorcontrib>Ernst, Robin E</creatorcontrib><creatorcontrib>Woods, Andrea</creatorcontrib><creatorcontrib>Forrest, Gail</creatorcontrib><creatorcontrib>An, Zhiqiang</creatorcontrib><creatorcontrib>Zaller, Dennis M</creatorcontrib><creatorcontrib>Strohl, William R</creatorcontrib><creatorcontrib>Luo, Cindy S</creatorcontrib><creatorcontrib>Czabotar, Peter E</creatorcontrib><creatorcontrib>Garrett, Thomas P J</creatorcontrib><creatorcontrib>Hilton, Douglas J</creatorcontrib><creatorcontrib>Nash, Andrew D</creatorcontrib><creatorcontrib>Zhang, Jian-Guo</creatorcontrib><creatorcontrib>Nicola, Nicos A</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><jtitle>Biochemical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Redpath, Nicholas T</au><au>Xu, Yibin</au><au>Wilson, Nicholas J</au><au>Fabri, Louis J</au><au>Baca, Manuel</au><au>Andrews, Arna E</au><au>Braley, Hal</au><au>Lu, Ping</au><au>Ireland, Cheryl</au><au>Ernst, Robin E</au><au>Woods, Andrea</au><au>Forrest, Gail</au><au>An, Zhiqiang</au><au>Zaller, Dennis M</au><au>Strohl, William R</au><au>Luo, Cindy S</au><au>Czabotar, Peter E</au><au>Garrett, Thomas P J</au><au>Hilton, Douglas J</au><au>Nash, Andrew D</au><au>Zhang, Jian-Guo</au><au>Nicola, Nicos A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Production of a human neutralizing monoclonal antibody and its crystal structure in complex with ectodomain 3 of the interleukin-13 receptor α1</atitle><jtitle>Biochemical journal</jtitle><addtitle>Biochem J</addtitle><date>2013-04-15</date><risdate>2013</risdate><volume>451</volume><issue>2</issue><spage>165</spage><epage>175</epage><pages>165-175</pages><issn>0264-6021</issn><eissn>1470-8728</eissn><abstract>Gene deletion studies in mice have revealed critical roles for IL (interleukin)-4 and -13 in asthma development, with the latter controlling lung airways resistance and mucus secretion. We have now developed human neutralizing monoclonal antibodies against human IL-13Rα1 (IL-13 receptor α1) subunit that prevent activation of the receptor complex by both IL-4 and IL-13. We describe the crystal structures of the Fab fragment of antibody 10G5H6 alone and in complex with D3 (ectodomain 3) of IL-13Rα1. Although the structure showed significant domain swapping within a D3 dimer, we showed that Arg(230), Phe(233), Tyr(250), Gln(252) and Leu(293) in each D3 monomer and Ser(32), Asn(102) and Trp(103) in 10G5H6 Fab are the key interacting residues at the interface of the 10G5H6 Fab-D3 complex. One of the most striking contacts is the insertion of the ligand-contacting residue Leu(293) of D3 into a deep pocket on the surface of 10G5H6 Fab, and this appears to be a central determinant of the high binding affinity and neutralizing activity of the antibody.</abstract><cop>England</cop><pmid>23384096</pmid><doi>10.1042/BJ20121819</doi><tpages>11</tpages></addata></record> |
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| subjects | Animals Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - immunology Antibodies, Monoclonal - metabolism Antibodies, Neutralizing - chemistry Antibodies, Neutralizing - immunology Antibodies, Neutralizing - metabolism Binding Sites - immunology Crystallography, X-Ray Dimerization Epitopes Humans Immunoglobulin Fab Fragments - chemistry Interleukin-13 - immunology Interleukin-13 - metabolism Interleukin-13 Receptor alpha1 Subunit - chemistry Interleukin-13 Receptor alpha1 Subunit - metabolism Interleukin-4 - immunology Interleukin-4 - metabolism Leucine - metabolism Mice Mice, Transgenic Protein Structure, Tertiary |
| title | Production of a human neutralizing monoclonal antibody and its crystal structure in complex with ectodomain 3 of the interleukin-13 receptor α1 |
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