Structure of the Discoidin Domain Receptor 1 Extracellular Region Bound to an Inhibitory Fab Fragment Reveals Features Important for Signaling
The discoidin domain receptors, DDR1 and DDR2, are constitutively dimeric receptor tyrosine kinases that are activated by triple-helical collagen. Aberrant DDR signaling contributes to several human pathologies, including many cancers. We have generated monoclonal antibodies (mAbs) that inhibit DDR1...
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| Veröffentlicht in: | Structure (London) 2012-04, Vol.20 (4), p.688-697 |
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| creator | Carafoli, Federico Mayer, Marie Cathrin Shiraishi, Kazushige Pecheva, Mira Anguelova Chan, Lai Yi Nan, Ruodan Leitinger, Birgit Hohenester, Erhard |
| description | The discoidin domain receptors, DDR1 and DDR2, are constitutively dimeric receptor tyrosine kinases that are activated by triple-helical collagen. Aberrant DDR signaling contributes to several human pathologies, including many cancers. We have generated monoclonal antibodies (mAbs) that inhibit DDR1 signaling without interfering with collagen binding. The crystal structure of the monomeric DDR1 extracellular region bound to the Fab fragment of mAb 3E3 reveals that the collagen-binding discoidin (DS) domain is tightly associated with the following DS-like domain, which contains the epitopes of all mAbs. A conserved surface patch in the DS domain outside the collagen-binding site is shown to be required for signaling. Thus, the active conformation of the DDR1 dimer involves collagen-induced contacts between the DS domains, in addition to the previously identified association of transmembrane helices. The mAbs likely inhibit signaling by sterically blocking the extracellular association of DDR1 subunits.
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► Monoclonal antibodies inhibit DDR1 signaling without blocking collagen binding ► The DDR1 extracellular region consists of a DS and a DS-like domain ► The collagen-binding DS domain contains a patch that is essential for signaling ► The mAbs bind to the DS-like domain, preventing formation of the active DDR dimer |
| doi_str_mv | 10.1016/j.str.2012.02.011 |
| format | Article |
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[Display omitted]
► Monoclonal antibodies inhibit DDR1 signaling without blocking collagen binding ► The DDR1 extracellular region consists of a DS and a DS-like domain ► The collagen-binding DS domain contains a patch that is essential for signaling ► The mAbs bind to the DS-like domain, preventing formation of the active DDR dimer</description><identifier>ISSN: 0969-2126</identifier><identifier>EISSN: 1878-4186</identifier><identifier>DOI: 10.1016/j.str.2012.02.011</identifier><identifier>PMID: 22483115</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antibodies, Neutralizing - chemistry ; Binding Sites ; Collagen - chemistry ; Collagen - genetics ; Crystallography, X-Ray ; Discoidin Domain Receptor 1 ; Discoidin Domain Receptors ; Flow Cytometry ; HEK293 Cells ; Humans ; Immunoglobulin Fab Fragments - chemistry ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits - antagonists & inhibitors ; Protein Subunits - chemistry ; Protein Subunits - genetics ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - chemistry ; Receptor Protein-Tyrosine Kinases - genetics ; Receptors, Mitogen - chemistry ; Receptors, Mitogen - genetics ; Recombinant Fusion Proteins - chemistry ; Recombinant Fusion Proteins - genetics ; Signal Transduction - genetics ; Transfection</subject><ispartof>Structure (London), 2012-04, Vol.20 (4), p.688-697</ispartof><rights>2012 Elsevier Ltd</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><rights>2012 ELL & Excerpta Medica. 2012 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c549t-800b8e008c44c7ef6c593f28a0a8a5c624da5f893ddc173060d796a4848a9fa03</citedby><cites>FETCH-LOGICAL-c549t-800b8e008c44c7ef6c593f28a0a8a5c624da5f893ddc173060d796a4848a9fa03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.str.2012.02.011$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,778,782,883,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22483115$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carafoli, Federico</creatorcontrib><creatorcontrib>Mayer, Marie Cathrin</creatorcontrib><creatorcontrib>Shiraishi, Kazushige</creatorcontrib><creatorcontrib>Pecheva, Mira Anguelova</creatorcontrib><creatorcontrib>Chan, Lai Yi</creatorcontrib><creatorcontrib>Nan, Ruodan</creatorcontrib><creatorcontrib>Leitinger, Birgit</creatorcontrib><creatorcontrib>Hohenester, Erhard</creatorcontrib><title>Structure of the Discoidin Domain Receptor 1 Extracellular Region Bound to an Inhibitory Fab Fragment Reveals Features Important for Signaling</title><title>Structure (London)</title><addtitle>Structure</addtitle><description>The discoidin domain receptors, DDR1 and DDR2, are constitutively dimeric receptor tyrosine kinases that are activated by triple-helical collagen. Aberrant DDR signaling contributes to several human pathologies, including many cancers. We have generated monoclonal antibodies (mAbs) that inhibit DDR1 signaling without interfering with collagen binding. The crystal structure of the monomeric DDR1 extracellular region bound to the Fab fragment of mAb 3E3 reveals that the collagen-binding discoidin (DS) domain is tightly associated with the following DS-like domain, which contains the epitopes of all mAbs. A conserved surface patch in the DS domain outside the collagen-binding site is shown to be required for signaling. Thus, the active conformation of the DDR1 dimer involves collagen-induced contacts between the DS domains, in addition to the previously identified association of transmembrane helices. The mAbs likely inhibit signaling by sterically blocking the extracellular association of DDR1 subunits.
[Display omitted]
► Monoclonal antibodies inhibit DDR1 signaling without blocking collagen binding ► The DDR1 extracellular region consists of a DS and a DS-like domain ► The collagen-binding DS domain contains a patch that is essential for signaling ► The mAbs bind to the DS-like domain, preventing formation of the active DDR dimer</description><subject>Antibodies, Neutralizing - chemistry</subject><subject>Binding Sites</subject><subject>Collagen - chemistry</subject><subject>Collagen - genetics</subject><subject>Crystallography, X-Ray</subject><subject>Discoidin Domain Receptor 1</subject><subject>Discoidin Domain Receptors</subject><subject>Flow Cytometry</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immunoglobulin Fab Fragments - chemistry</subject><subject>Models, Molecular</subject><subject>Protein Binding</subject><subject>Protein Multimerization</subject><subject>Protein Structure, Secondary</subject><subject>Protein Structure, Tertiary</subject><subject>Protein Subunits - antagonists & inhibitors</subject><subject>Protein Subunits - chemistry</subject><subject>Protein Subunits - genetics</subject><subject>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Receptor Protein-Tyrosine Kinases - chemistry</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Receptors, Mitogen - chemistry</subject><subject>Receptors, Mitogen - genetics</subject><subject>Recombinant Fusion Proteins - chemistry</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Signal Transduction - genetics</subject><subject>Transfection</subject><issn>0969-2126</issn><issn>1878-4186</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-KFDEQxoMo7rj6AF4kN730WEn_SxCEdXdHBxYEV8-hJp3uydCdjEl6cF_CZzbDrIteFgrqUL_6Uvk-Ql4zWDJgzfvdMqaw5MD4EnIx9oQsmGhFUTHRPCULkI0sOOPNGXkR4w4AeA3wnJxxXomSsXpBft-mMOs0B0N9T9PW0CsbtbeddfTKT5jbN6PNPvlAGb3-lQJqM47ziCEPBusd_eRn19HkKTq6dlu7sRm-oyvc0FXAYTIuZfRgcIx0ZfD4VqTrae9Dwjzqs_KtHRyO1g0vybM-c-bVfT8nP1bX3y-_FDdfP68vL24KXVcyFQJgIwyA0FWlW9M3upZlzwUCCqx1w6sO617Isus0a0tooGtlg5WoBMoeoTwnH0-6-3kzmU7nGwOOah_shOFOebTq_4mzWzX4gypLDi3jWeDtvUDwP2cTk5qyb9kZdMbPUUlZMihZ02by3aNkTrKVdQtwRNkJ1cHHGEz_cBCDI9eoncqJq2PiCnIxlnfe_PuTh42_EWfgwwkw2c-DNUFFbY3TprPB6KQ6bx-R_wNn876S</recordid><startdate>20120404</startdate><enddate>20120404</enddate><creator>Carafoli, Federico</creator><creator>Mayer, Marie Cathrin</creator><creator>Shiraishi, Kazushige</creator><creator>Pecheva, Mira Anguelova</creator><creator>Chan, Lai Yi</creator><creator>Nan, Ruodan</creator><creator>Leitinger, Birgit</creator><creator>Hohenester, Erhard</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</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>7T5</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120404</creationdate><title>Structure of the Discoidin Domain Receptor 1 Extracellular Region Bound to an Inhibitory Fab Fragment Reveals Features Important for Signaling</title><author>Carafoli, Federico ; Mayer, Marie Cathrin ; Shiraishi, Kazushige ; Pecheva, Mira Anguelova ; Chan, Lai Yi ; Nan, Ruodan ; Leitinger, Birgit ; Hohenester, Erhard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c549t-800b8e008c44c7ef6c593f28a0a8a5c624da5f893ddc173060d796a4848a9fa03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antibodies, Neutralizing - chemistry</topic><topic>Binding Sites</topic><topic>Collagen - chemistry</topic><topic>Collagen - genetics</topic><topic>Crystallography, X-Ray</topic><topic>Discoidin Domain Receptor 1</topic><topic>Discoidin Domain Receptors</topic><topic>Flow Cytometry</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Immunoglobulin Fab Fragments - chemistry</topic><topic>Models, Molecular</topic><topic>Protein Binding</topic><topic>Protein Multimerization</topic><topic>Protein Structure, Secondary</topic><topic>Protein Structure, Tertiary</topic><topic>Protein Subunits - antagonists & inhibitors</topic><topic>Protein Subunits - chemistry</topic><topic>Protein Subunits - genetics</topic><topic>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Receptor Protein-Tyrosine Kinases - chemistry</topic><topic>Receptor Protein-Tyrosine Kinases - genetics</topic><topic>Receptors, Mitogen - chemistry</topic><topic>Receptors, Mitogen - genetics</topic><topic>Recombinant Fusion Proteins - chemistry</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Signal Transduction - genetics</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carafoli, Federico</creatorcontrib><creatorcontrib>Mayer, Marie Cathrin</creatorcontrib><creatorcontrib>Shiraishi, Kazushige</creatorcontrib><creatorcontrib>Pecheva, Mira Anguelova</creatorcontrib><creatorcontrib>Chan, Lai Yi</creatorcontrib><creatorcontrib>Nan, Ruodan</creatorcontrib><creatorcontrib>Leitinger, Birgit</creatorcontrib><creatorcontrib>Hohenester, Erhard</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Structure (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Carafoli, Federico</au><au>Mayer, Marie Cathrin</au><au>Shiraishi, Kazushige</au><au>Pecheva, Mira Anguelova</au><au>Chan, Lai Yi</au><au>Nan, Ruodan</au><au>Leitinger, Birgit</au><au>Hohenester, Erhard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure of the Discoidin Domain Receptor 1 Extracellular Region Bound to an Inhibitory Fab Fragment Reveals Features Important for Signaling</atitle><jtitle>Structure (London)</jtitle><addtitle>Structure</addtitle><date>2012-04-04</date><risdate>2012</risdate><volume>20</volume><issue>4</issue><spage>688</spage><epage>697</epage><pages>688-697</pages><issn>0969-2126</issn><eissn>1878-4186</eissn><abstract>The discoidin domain receptors, DDR1 and DDR2, are constitutively dimeric receptor tyrosine kinases that are activated by triple-helical collagen. Aberrant DDR signaling contributes to several human pathologies, including many cancers. We have generated monoclonal antibodies (mAbs) that inhibit DDR1 signaling without interfering with collagen binding. The crystal structure of the monomeric DDR1 extracellular region bound to the Fab fragment of mAb 3E3 reveals that the collagen-binding discoidin (DS) domain is tightly associated with the following DS-like domain, which contains the epitopes of all mAbs. A conserved surface patch in the DS domain outside the collagen-binding site is shown to be required for signaling. Thus, the active conformation of the DDR1 dimer involves collagen-induced contacts between the DS domains, in addition to the previously identified association of transmembrane helices. The mAbs likely inhibit signaling by sterically blocking the extracellular association of DDR1 subunits.
[Display omitted]
► Monoclonal antibodies inhibit DDR1 signaling without blocking collagen binding ► The DDR1 extracellular region consists of a DS and a DS-like domain ► The collagen-binding DS domain contains a patch that is essential for signaling ► The mAbs bind to the DS-like domain, preventing formation of the active DDR dimer</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22483115</pmid><doi>10.1016/j.str.2012.02.011</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Antibodies, Neutralizing - chemistry Binding Sites Collagen - chemistry Collagen - genetics Crystallography, X-Ray Discoidin Domain Receptor 1 Discoidin Domain Receptors Flow Cytometry HEK293 Cells Humans Immunoglobulin Fab Fragments - chemistry Models, Molecular Protein Binding Protein Multimerization Protein Structure, Secondary Protein Structure, Tertiary Protein Subunits - antagonists & inhibitors Protein Subunits - chemistry Protein Subunits - genetics Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - chemistry Receptor Protein-Tyrosine Kinases - genetics Receptors, Mitogen - chemistry Receptors, Mitogen - genetics Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics Signal Transduction - genetics Transfection |
| title | Structure of the Discoidin Domain Receptor 1 Extracellular Region Bound to an Inhibitory Fab Fragment Reveals Features Important for Signaling |
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